Systems and methods for enabling appetite modulation and/or improving dietary compliance using percutaneous electrical neurostimulation

ABSTRACT

A wearable, percutaneous device for suppressing appetite or hunger in a patient includes a microprocessor, electrical stimulator and at least one percutaneous electrode implanted and configured to deliver electrical stimulation through the patient&#39;s skin. The percutaneous device includes a pad and at least one needle, in which the electrode is disposed, for secure placement of the device within the skin of a patient. The percutaneous device is adapted to provide electrical stimulation as per stimulation protocols and to communicate wirelessly with a companion control device configured to monitor and record appetite patterns of the patient. The control device is also configured to monitor, record, and modify stimulation parameters of the stimulation protocols.

CROSS-REFERENCE

The present specification is a continuation-in-part of U.S. patentapplication Ser. No. 15/052,791, entitled “Systems and Methods forEnabling Appetite Modulation and/or Improving Dietary Compliance Usingan Electro-Dermal Patch, filed on Feb. 24, 2016, which, in turn relieson U.S. Patent Provisional Application No. 62/120,067, entitled“Dermatome Stimulation System” and filed on Feb. 24, 2015, for priority.

The present specification is a continuation-in-part of U.S. patentapplication Ser. No. 15/052,784, entitled “Systems and Methods forEnabling Appetite Modulation and/or Improving Dietary Compliance Usingan Electro-Dermal Patch, filed on Feb. 24, 2016, which, in turn, relieson U.S. Patent Provisional Application No. 62/120,082, entitled“Dermatome Stimulation Methods” and filed on Feb. 24, 2015, forpriority.

The present specification also relies on U.S. Patent ProvisionalApplication No. 62/189,800, entitled “Dermatome Stimulation Method” andfiled on Jul. 8, 2015, for priority. The present specification alsorelies on U.S. Patent Provisional Application No. 62/189,805, entitled“Dermatome Stimulation System” and filed on Jul. 8, 2015, for priority.

In addition, the above-mentioned non-provisional U.S patent applicationsalso rely on the following applications, for priority:

U.S. Patent Provisional Application No. 62/133,526, entitled “DermatomeStimulation System” and filed on Mar. 16, 2015, for priority. U.S.Patent Provisional Application No. 62/133,530, entitled “DermatomeStimulation Method” and filed on Mar. 16, 2015, for priority.

U.S. Patent Provisional Application No. 62/141,328, entitled “DermatomeStimulation System” and filed on Apr. 1, 2015, for priority. U.S. PatentProvisional Application No. 62/141,333, entitled “Dermatome StimulationMethod” and filed on Apr. 1, 2015, for priority.

U.S. Patent Provisional Application No. 62/161,353, entitled “DermatomeStimulation System” and filed on May 14, 2015, for priority.

U.S. Patent Provisional Application No. 62/161,362, entitled “DermatomeStimulation Method” and filed on May 14, 2015, for priority.

The present specification also relies on U.S. Patent ProvisionalApplication No. 62/237,356, entitled “Systems and Methods for EnablingAppetite Modulation Using Transcutaneous Electrical Neurostimulation”and filed on Oct. 5, 2015, for priority.

The present specification also relies on U.S. Patent ProvisionalApplication No. 62/240,808, entitled “Systems and Methods for EnablingAppetite Modulation Using an Electro-Dermal Patch” and filed on Oct. 13,2015, for priority.

The present specification also relies on U.S. Patent ProvisionalApplication No. 62/242,944, entitled “Systems and Methods for EnablingAppetite Modulation Using an Electro-Dermal Patch” and filed on Oct. 16,2015, for priority.

The present specification also relies on U.S. Patent ProvisionalApplication No. 62/242,957, entitled “Systems and Methods for EnablingAppetite Modulation Using an Electro-Dermal Patch” and filed on Oct. 16,2015, for priority.

The present specification also relies on U.S. Patent ProvisionalApplication No. 62/246,526, entitled “Systems and Methods for EnablingAppetite Modulation Using an Electro-Dermal Patch” and filed on Oct. 26,2015, for priority.

The present specification also relies on U.S. Patent ProvisionalApplication No. 62/247,113, entitled “Systems and Methods for EnablingAppetite Modulation Using an Electro-Dermal Patch” and filed on Oct. 27,2015, for priority.

The present specification also relies on U.S. Patent ProvisionalApplication No. 62/248,059, entitled “Systems and Methods for EnablingPain Management Using an Electro-Dermal Patch” and filed on Oct. 29,2015, for priority.

All of the above-mentioned applications are herein incorporated byreference in their entirety.

FIELD

The present specification relates generally to systems and methods ofmodulating a patient's appetite, hunger, satiety level, satiation level,or fullness level in a user by delivering electrical stimulation to apredetermined area of the user's anatomy in a manner that is convenient,easy to use, and amenable to increased patient compliance. Moreparticularly, the present specification relates to percutaneouselectrical stimulation devices comprising low profile, wearable,disposable percutaneous skin patches that are easily programmable andmonitorable using a mobile handheld device, and programmed to stimulatea patient's nerves in a manner that enables appetite or hunger control,modulation or suppression, avoids nausea, dyspepsia, minimizeshabituation and enables increased compliance with a dietary regimen. Thepresent specification further relates to a low profile, wearable,disposable percutaneous skin patch that is capable of integrating with,and being controlled by, a plurality of different hardware devices orsoftware applications depending on the type, extent, nature and scope ofthe appetite, hunger, satiety level, satiation level, or fullness levelmodulation desired, the nature and degree of dietary compliancerequired, the amount of weight loss desired and/or the need for longterm weight maintenance.

BACKGROUND

The potential benefits of enabling a user to modulate, suppress orcontrol his appetite include decreasing a person's excess weight and,thereby potentially beneficially affecting all of the health problemsassociated therewith, as further discussed below. The same potentialbenefits apply to modulating or otherwise controlling a person's hunger,satiety level, satiation level, and degree of fullness.

Being obese, or overweight, is a condition that often results from animbalance between food intake and caloric expenditure. Excessive weightincreases the likelihood of several additional risks includingcardiovascular complications (such as hypertension and hyperlipidemia),gallbladder disease, metabolic syndrome, cancer, polycystic ovarydisease, pregnancy-related complications, arthritis-relatedcomplications and other orthopedic complications caused by stress onbody joints. Obesity is also thought to be a primary cause of type 2diabetes (T2DM) in many ethnicities.

In “Effect of Somatovisceral Reflexes and Selective DermatomalStimulation on Postcibal Antral Pressure Activity”, Camilleri et al.,sustained somatic stimulation by a transcutaneous electrical nervestimulation (TENS) device was applied to the skin of human volunteerswhile simultaneously monitoring their upper gastrointestinal phasicpressure activity, extra-intestinal vasomotor indices, and plasma levelsof putative humoral mediators of autonomic reflexes. Camilleri positsthat “somatovisceral reflex alteration of gastric motility may also beelicited in humans . . . and suggests that a sustained somatic stimuluswould also result in impaired antral phasic pressure response to asolid-liquid meal.” However, Camilleri's approach requires sustainedpainful somatic stimulation and, accordingly, from a compliancestandpoint, is simply not a feasible therapeutic approach.

U.S. Pat. No. 7,200,443 discloses “electrode pads . . . situatedproximate to the thoracic vertebrae and the preganglionic greatersplanchnic nerve fibers of the spine to stimulate the postganglionicsympathetic nerve pathways innervating the stomach.” The electrode padsare “positioned at or near the top and bottom, respectively, of thethoracic spine”. Because the electrodes are placed on the spine, it isdifficult for a person to place, activate, or maintain the device on hisown, reduces compliance, and is not practically sustainable as a therapyfor people who are overweight.

Additionally such therapies require a medical professional to place thedevice and/or administer the therapy, including programming the device.The patient must visit the medical professional at the onset oftreatment to have the device placed and then weekly thereafter to havethe therapy administered and/or device programming modified. Therequirement for such frequent doctor visits is inconvenient for mostpatients and can have a detrimental effect on patient compliance.

Additionally, such prior approaches using electrical, externalstimulation to suppress appetite do not have a combination of thefollowing characteristics effective to treat a patient: wearability;real-time or near real-time feedback from the patient (e.g. food intake,exercise, hunger) or from wearable devices, for example, a device, withphysiological sensors, configured to be worn on the human body, such asaround the wrist, in order to monitor, acquire, record, and/or transmitthe physiological data; the ability to stimulate multiple times per dayor week; daily, or on-demand, feedback from the device to the patientwith respect to dietary compliance, exercise, calories burned; storageof stimulation parameters and other real-time inputs; and an electricalstimulation profile and a footprint conducive to wearability. Inaddition, prior art therapies which have some degree of flexibilityinclude an electrode which must be tethered via cables to a control orpower box. Prior art therapies which are wireless are typically bulky,inflexible, and not amenable to being worn for long periods of time.

Because successful weight loss is, in the end, a matter of achieving ahigh degree of compliance with a dietary regimen, it is absolutelycritical for a successful device to go beyond mere appetite suppressionand combine wearability, physical comfort, ease of use, and integrationof numerous data sources to provide a holistic and real-time view into aperson's dietary compliance, in addition to effectively modulating theindividual's appetite, hunger, satiety level, satiation level, orfullness.

Therefore, there is a need for a low profile, long lasting electricalneuro-stimulation device which is programmable, and is effective tocause appetite or hunger control, modulation or suppression whileminimizing any accompanying nausea, dyspepsia and habituation. There isalso a need for a device that can effectively integrate appetitemanagement data with conventional weight management information, such ascaloric expenditure and consumption.

There is a need for an electrical neuro-stimulation device which iswearable and can be controlled and programmed. There is also a need foran electrical neuro-stimulation device which includes real-time or nearreal-time feedback from patient parameters including, but not limitedto, exercise, diet, hunger, appetite, well-being and which will be ableto obtain real-time or near real-time feedback from other wearabledevices, for example, a device, with physiological sensors, configuredto be worn on the human body, such as around the wrist, in order tomonitor, acquire, record, and/or transmit the physiological data,allowing for frequent adjustability and customization of therapy tosuppress appetite and therefore treat conditions of obesity,over-weight, eating disorders, metabolic syndrome. There is a need foran electro-stimulation device configured to intelligently trigger andinitiate stimulation automatically and without on-going management by auser. There is a need for an electrical neuro-stimulation device havingthe ability to stimulate multiple times per day or per week,accelerating treatment effect and efficacy. There is a need for anelectrical neuro-stimulation device which provides daily feedback fromthe device to the patient on such parameters as dietary compliance, andcalories burned.

In addition, there is a need for an electrical neuro-stimulation devicecapable of storing stimulation parameters and other real-time inputs,such as diary and exercise monitoring, to provide a physician and thepatient with real-time records and treatment profiles. Inputs from theelectrical neuro-stimulation device and from other sources ofinformation, for example, a device, with physiological sensors,configured to be worn on the human body, such as around the wrist, inorder to monitor, acquire, record, and/or transmit the physiologicaldata would be stored.

There is also a need to allow physicians to be able to flexibly programan electrical neuro-stimulation device and still direct the patient,allowing the patient to adjust device parameters (for greater patientindependence) but within restricted bounds or predetermined parameters.

There is also a need for an electrical neuro-stimulation device whichtargets appetite or hunger suppression, does not require implantation,and does not require wires or remote electrodes to provide stimulation.There is a need for an electrical neuro-stimulation device which isremotely programmable, yet wireless, can flex at any point along itsbody, is waterproof, and is configured for extended or permanentwearability. There is also a need for a wearable electricalneuro-stimulation device directed toward suppressing post-prandialglucose levels and effectively modulating a plurality of hormones andmicrobiota related to gastrointestinal functionality. There is a needfor an electrical neuro-stimulation device having a size, shape, andweight, and being composed of materials that effectively allow thedevice to be wearable. Such a device would eliminate the need forstimulation parameters requiring large power needs (which would makewearability impractical or impossible). There is also a need for anelectrical neuro-stimulation device which is controllable by a companiondevice (such as a smartphone) and includes no visible or tactile userinterface on the stimulation device itself. There is a need for anelectrical neuro-stimulation device having unique electrical stimulationand footprint, based on electrode design and stimulation parameters,which would allow users to comfortably wear the device.

There is also a need for a holistic approach to managing a patient'scaloric consumption and expenditure profile. Conventional approachesfocus on caloric intake but do not analyze, monitor, or otherwise gatherdata on the important precursor to caloric intake, namely appetite orhunger levels. There are untapped benefits to integrating data relatingto the appetite, hunger and/or craving levels, active suppression orcontrol over appetite, caloric intake, weight gain, and caloricexpenditure. These and other benefits shall be described in relation tothe detailed description and figures.

SUMMARY

The following embodiments and aspects thereof are described andillustrated in conjunction with systems, tools and methods, which aremeant to be exemplary and illustrative, and not limiting in scope. Thepresent application discloses numerous embodiments.

The device may be used to treat a condition including any one ofobesity, excess weight, eating disorders, metabolic syndrome anddiabetes. In accordance with various aspects of the presentspecification, the neuro-stimulation device enables treating people withBMI (Body Mass Index) of 25 or greater (overweight being 25-30, obesebeing 30 and above, and morbid obesity being above 35).

In some embodiments, the present specification discloses an electricalstimulation system configured to modulate at least one of a patient'sappetite, hunger, level of satiety, or level of satiation levelcomprising: a percutaneous electrical dermal patch adapted to be adheredto the patient's epidermal layer, wherein said electrical dermal patchcomprises a controller, at least one electrode adapted to be implantedto a depth of 0.1 mm to 30 mm within said patient's skin, a pulsegenerator in electrical communication with the controller and said atleast one electrode; and a transceiver in communication with at leastone of said controller and pulse generator; and a plurality ofprogrammatic instructions, stored in a non-transient computer readablememory of a device physically separate from said percutaneous electricaldermal patch, wherein, when executed, said programmatic instructionsacquire patient status data, generate a modulation signal based uponsaid patient status data, wherein said modulation signal comprisesinstructions for modulating at least one of a pulse width, a pulseamplitude, a pulse frequency, a pulse shape, a duty cycle, a sessionduration, and a session frequency, and wirelessly transmit saidmodulation signal from the device to the transceiver.

Optionally, the electrical stimulation system further comprises a secondelectrode positioned on a surface of the patient's epidermal layer.

Optionally, the electrical stimulation system further comprises a secondpercutaneous electrode adapted to be implanted to a depth of 0.1 mm to30 mm within said patient's skin.

Optionally, the pulse generator is configured to generate a plurality ofelectrical pulses and a corresponding electrical field, wherein theelectrical field is adapted to penetrate a range of 0.1 mm to 30 mmthrough the patient's skin.

Optionally, the plurality of electrical pulses comprise a pulse width ina range of 10 μsec to 100 msec, a pulse amplitude in a range of 100 μAto 500 mA, and a pulse frequency in a range of 1 Hz to 10,000 Hz.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that a post-stimulation dailycaloric intake of said patient decreases relative to a pre-stimulationdaily caloric intake of said patient, wherein said pre-stimulation dailycaloric intake is a function of an amount of calories consumed by thepatient over a first predefined period of time prior to stimulation, andwherein said post-stimulation daily caloric intake is a function of anamount of calories consumed by the patient over a second predefinedperiod of time equal in duration to the first predefined period of time,after stimulation is initiated.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that a post-stimulation dailycaloric intake of said patient is less than 99% of a pre-stimulationdaily caloric intake of said patient, wherein said pre-stimulation dailycaloric intake is a function of an amount of calories consumed by thepatient over a first predefined period of time prior to stimulation, andwherein said post-stimulation daily caloric intake is a function of anamount of calories consumed by the patient over a second predefinedperiod of time equal in duration to the first predefined period of time,after stimulation is initiated.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, the patient's compliance with a target daily caloric intakeincreases relative to the patient's compliance with the target dailycaloric intake before stimulation.

Optionally, said patient status data comprises at least one of thepatient's hunger, the patient's hunger appetite, the patient's satietylevel, the patient's satiation level, and a degree of well-being beingexperienced by the patient.

Optionally, said well-being level comprises at least one of a degree ofnausea being experienced by the patient and a degree of dyspepsia beingexperienced by the patient.

Optionally, when executed, said programmatic instructions acquire afirst stimulation protocol and use said first stimulation protocol togenerate the modulation signal.

Optionally, when executed, said programmatic instructions acquire asecond stimulation protocol, wherein said second stimulation protocol isdifferent from the first stimulation protocol, and, using said secondstimulation protocol, generate a second modulation signal, wherein saidsecond modulation signal comprises instructions for modulating at leastone of the pulse width, the pulse amplitude, the pulse frequency, thepulse shape, the duty cycle, the session duration, and the sessionfrequency.

Optionally, when executed, said programmatic instructions wirelesslytransmit said second modulation signal from the device to the electricaldermal patch.

Optionally, the percutaneous electrical dermal patch is configured touse the second modulation signal to modify at least one of said pulsewidth, pulse amplitude, pulse frequency, pulse shape, duty cycle,session duration, and session frequency to yield a second pulse width, asecond pulse amplitude, a second pulse frequency, a second pulse shape,a second duty cycle, a second session duration, or a second sessionfrequency, wherein at least one of the second pulse width is differentfrom the first pulse width, the second pulse amplitude is different fromthe first pulse amplitude, the second pulse frequency is different fromthe first pulse frequency, the second pulse shape is different from thefirst pulse shape, the second duty cycle is different from the firstduty cycle, the second session duration is different from the firstsession duration, and the second session frequency is different from thefirst session frequency.

Optionally, said controller, pulse generator, and transceiver arepositioned in a first housing and the at least one electrode ispositioned outside said first housing.

Optionally, said controller and transceiver are positioned in a firsthousing and said pulse generator and the at least one electrode arepositioned outside said first housing.

Optionally, the electrical field is adapted to contact at least one ofthe patient's T2 frontal and lateral thoracic dermatome, T3 frontal andlateral thoracic dermatome, T4 frontal and lateral thoracic dermatome,T5 frontal and lateral thoracic dermatome, T6 frontal and lateralthoracic dermatome, T7 frontal and lateral thoracic dermatome, T8frontal and lateral thoracic dermatome, T9 frontal and lateral thoracicdermatome, or T10 frontal and lateral thoracic dermatome.

Optionally, the electrical field is adapted to contact at least one ofthe patient's T2 frontal and lateral thoracic dermatome, T3 frontal andlateral thoracic dermatome, T4 frontal and lateral thoracic dermatome,T5 frontal and lateral thoracic dermatome, T6 frontal and lateralthoracic dermatome, T7 frontal and lateral thoracic dermatome, T8frontal and lateral thoracic dermatome, T9 frontal and lateral thoracicdermatome, and T10 frontal and lateral thoracic dermatome and is notpositioned within a range of 0.1 mm to 25 mm from any one of thepatient's T2 posterior thoracic dermatome, T3 posterior thoracicdermatome, T4 posterior thoracic dermatome, T5 posterior thoracicdermatome, T6 posterior thoracic dermatome, T7 posterior thoracicdermatome, T8 posterior thoracic dermatome, T9 posterior thoracicdermatome, and T10 posterior thoracic dermatome.

Optionally, the electrical field is adapted to contact at least one ofthe patient's C8 anterior or posterior dermatome located on thepatient's hand, wrist, elbow, and fingers, C8 anterior or posteriordermatome located on the patient's arm, C8 dermatome located on thepatient's upper trunk, T1 anterior or posterior dermatome located on thepatient's arm, T1 anterior or posterior dermatome located on thepatient's wrist, elbow, and hand, and T1 anterior or posterior dermatomelocated on the patient's upper trunk is electrically stimulated.

Optionally, the electrical stimulation system further comprises anadhesive layer positioned on the bottom surface of the electrical dermalpatch, such that when the adhesive layer is adhered to the patient'sskin, the electrical dermal patch has an average minimum peel strengthin a range of 1.3 to 1.7 newtons.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after receiving at least onestimulation session, the appetite of said patient is less than theappetite of said patient prior to receiving said at least onestimulation session.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, the patient's appetite decreases, over a predefined periodof time, relative to the patient's appetite before stimulation and anausea level of the patient does not increase, over said predefinedperiod of time, relative to the nausea level of the patient beforestimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, the patient's appetite decreases, over a predefined periodof time, relative to the patient's appetite before stimulation, whereinat least one of a dyspepsia level of the patient or a nausea level ofthe patient does not increase, over said predefined period of time,relative to at least one of the dyspepsia level or the nausea level ofthe patient before stimulation, and wherein said at least onestimulation does not cause the patient to experience a pain sensation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a total body weight of the patient reduces by at least 1%relative to a total body weight of the patient before stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, an excess body weight of the patient reduces by at least 1%relative to an excess body weight of the patient before stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a total body weight of the patient reduces by at least 1%relative to a total body weight of the patient before stimulation and awell-being level of the patient does not reduce more than 5% relative toa well-being level of the patient before stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, the patient's appetite decreases, over a predefined periodof time, relative to the patient's appetite before stimulation and anausea level of the patient does not increase by more than 10%, oversaid predefined period of time, relative to the nausea level of thepatient before stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, the patient's hunger decreases, over a predefined period oftime, relative to the patient's hunger before stimulation and a nausealevel of the patient does not increase by more than 10%, over saidpredefined period of time, relative to the nausea level of the patientbefore stimulation.

Optionally, said housing is covered by at least one polymer having ahardness measure of 30-70 on a subzero shore scale.

Optionally, said housing is encased in at least one polymer having atensile modulus of 15 to 55 psi.

Optionally, the housing has a substantially linear profile, a width of 4inches or less, a length of 8 inches or less, and a height of 1 inchesor less.

Optionally, the percutaneous electrical dermal patch has a volume in arange of 0.25 in³ to 10 in³.

Optionally, the percutaneous electrical dermal patch has a weight in arange of 5 grams to 250 grams.

Optionally, the percutaneous electrical dermal patch further comprises apower source.

Optionally, the percutaneous electrical dermal patch further comprisesan impedance sensor configured to determine an electrode integrity ofthe at least one electrode.

Optionally, the pulse generator is configured to generate a plurality ofelectrical pulses and a corresponding electrical field, wherein theelectrical field is adapted to contact at least one of the patient's C5,C6, C7, C8, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, and T12dermatomes.

Optionally, the pulse generator is configured to generate a plurality ofelectrical pulses and a corresponding electrical field, wherein theelectrical field is adapted to contact a portion of at least one of thepatient's C5, C6, C7, C8, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11,and T12 frontal and lateral dermatomes and wherein the electrical fieldis not adapted to contact any portion of the patient's C5, C6, C7, C8,T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, and T12 posteriordermatomes.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a fasting glucose level of the patient reduces to a levelequal to or below 100 mg/dl from a level above 100 mg/dl beforestimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a pre-prandial ghrelin level of the patient reduces by atleast 1% relative to a pre-prandial ghrelin level of the patient beforestimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a post-prandial ghrelin level of the patient reduces by atleast 1% relative to a post-prandial ghrelin level of the patient beforestimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a glucagon-like peptide-1 level of the patient increases byat least 1% relative to a glucagon-like peptide-1 level of the patientbefore stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a leptin level of the patient increases by at least 1%relative to a leptin level of the patient before stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a peptide YY level of the patient increases by at least 1%relative to a peptide YY level of the patient before stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a lipopolysaccharide level of the patient reduces by atleast 1% relative to a lipopolysaccharide level of the patient beforestimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a motilin-related peptide level of the patient reduces byat least 1% relative to a motilin-related peptide level of the patientbefore stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a cholecystokinin level of the patient increases by atleast 1% relative to a cholecystokinin level of the patient beforestimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a resting metabolic rate of the patient increases by atleast 1% relative to a resting metabolic rate of the patient beforestimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a plasma-beta endorphin level of the patient increases byat least 1% relative to a plasma-beta endorphin level of the patientbefore stimulation.

Optionally, the electrical dermal patch further comprises a housing andwherein at least one of the controller and the pulse generator islocated within the housing.

Optionally, the at least one electrode is removably connected to anexterior surface of the housing.

Optionally, the electrical stimulation further comprises a circuit boardpositioned within said housing, wherein the controller and the pulsegenerator are positioned on the circuit board and wherein the circuitboard has a maximum area of 5 in².

Optionally, the circuit board comprises a dielectric laminate having nomore than three layers and having a thickness no greater than 0.05inches.

Optionally, said power source is two stacked batteries having a voltagein a range of 1.0 V to 8.0 V.

Optionally, the electrical dermal patch has an ingress protection ratingof at least IPX4.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, the patient's daily caloric intake decreases to a range of600 to 1600 calories.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, the patient's daily caloric intake decreases from over 2000calories per day to under 2000 calories per day.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, an amount of the patient's antral motility reduces relativeto the patient's antral motility before stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, an amount of the patient's gastric motility reducesrelative to the patient's gastric motility before stimulation.

Optionally, at least one of said pulse width, said pulse amplitude, andsaid pulse frequency are defined such that, after at least onestimulation, a rate of the patient's gastric emptying reduces relativeto a rate of the patient's gastric emptying before stimulation.

The aforementioned and other embodiments of the present specificationshall be described in greater depth in the drawings and detaileddescription provided below.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features and advantages of the present specificationwill be further appreciated, as they become better understood byreference to the following detailed description when considered inconnection with the accompanying drawings:

FIG. 1A is a block diagram of a system for stimulating nerves and nerveendings in body tissue, in accordance with various embodiments of thepresent specification;

FIG. 1B is a block diagram of a system for stimulating or modulatingnerves and nerve endings in body tissues, in accordance with anotherembodiment of the present specification;

FIG. 1C is a block diagram of a system for stimulating or modulatingnerves and nerve endings in body tissues, in accordance with yet anotherembodiment of the present specification;

FIG. 1D is a block diagram of a system for stimulating or modulatingnerves and nerve endings in body tissues, in accordance with yet anotherembodiment of the present specification;

FIG. 1E is a block diagram of a system for stimulating or modulatingnerves and nerve endings in body tissues, in accordance with stillanother embodiment of the present specification;

FIG. 1F is a block diagram of a system for stimulating or modulatingnerves and nerve endings in body tissues, in accordance with yet anotherembodiment of the present specification;

FIG. 1G is a flowchart illustrating a plurality of exemplary steps of amethod of self-implantation of a neuro-stimulation PEDP device, inaccordance with an embodiment of the present specification;

FIG. 1H is a perspective view of an array of micro-needle basedelectrodes mounted on a base;

FIG. 2A is a perspective view of a neuro-stimulation device configuredto provide electrical stimulation therapy, in accordance with someembodiments;

FIG. 2B illustrates an angle of insertion of a percutaneous electrodeinto a user's epidermal layer;

FIG. 2C is a perspective view of a percutaneous electrode insertionsystem, in accordance with some embodiments;

FIG. 3A is a side view illustration of a neuro-stimulation percutaneouselectrical dermal patch (PEDP) device, in accordance with oneembodiment;

FIG. 3B is a side view illustration of another neuro-stimulation PEDPdevice, in accordance with one embodiment;

FIG. 3C is a side view illustration of yet another neuro-stimulationPEDP device configured to provide electrical stimulation therapy, inaccordance with one embodiment;

FIG. 3D is a side view illustration of yet another neuro-stimulationPEDP device, in accordance with another embodiment of the presentspecification;

FIG. 3E is an illustration of a percutaneous multi-electrode array thatmay be employed with the devices of the present specification;

FIG. 4 is a block diagram of a mobile electronics platform that may beemployed with the devices of the present specification;

FIG. 5A is an illustration of a PEDP device that receives wirelessenergy for stimulation, in accordance with one embodiment;

FIG. 5B is an illustration of another PEDP device that receives wirelessenergy for stimulation, in accordance with one embodiment;

FIG. 6A illustrates an neuro-stimulation device of the presentspecification, configured as a percutaneous skin patch, placed at alateral thoracic dermatome and being wirelessly controlled by asmartphone, in accordance with various embodiments;

FIG. 6B is a schematic diagram of a plurality of percutaneouselectro-dermal patch users with companion devices shared over a commonnetwork connection, in accordance with one embodiment of the presentspecification;

FIG. 6C is a flow chart listing the steps in one embodiment of a methodof aggregating, organizing, and analyzing stimulation parameters andpatient hunger, appetite, and well-being scores for a plurality ofpatients, each having a PEDP device with linked companion deviceconnected to an aggregate patient network;

FIG. 6D is a flow chart illustrating the steps involved in using one ormore downloadable applications to configure and reconfigure stimulationprovided by a percutaneous electro-dermal patch (PEDP) device, inaccordance with one embodiment of the present specification;

FIG. 6E is a flow chart illustrating the steps involved in a method of acompanion device verifying and/or authenticating data transmissionreceived from a remote server, in accordance with some embodiments ofthe present specification;

FIG. 6F is a flow chart illustrating the steps involved in a method ofencrypting, authenticating, and/or verifying data transmissions betweena PEDP, companion device, and remote server based on FDA approval statusof the PEDP, in accordance with some embodiments of the presentspecification;

FIG. 7 is a screen shot of a companion device depicting a diary widget,in accordance with one embodiment of the present specification;

FIG. 8 is a screen shot of a companion device depicting a list view ofdiary entries, in accordance with one embodiment of the presentspecification;

FIG. 9 is a screen shot of a companion device depicting a calendar viewof diary entries, in accordance with one embodiment of the presentspecification;

FIG. 10 is a screen shot of a companion device depicting a quick entrybuttons view, in accordance with one embodiment of the presentspecification;

FIG. 11 is a screen shot of a companion device depicting an appetiteentry screen, in accordance with one embodiment of the presentspecification;

FIG. 12 is a screen shot of a companion device depicting an exerciseentry screen, in accordance with one embodiment of the presentspecification;

FIG. 13 is a screen shot of a companion device depicting a hunger entryscreen, in accordance with one embodiment of the present specification;

FIG. 14 is a screen shot of a companion device depicting a stimulationsession entry screen, in accordance with one embodiment of the presentspecification;

FIG. 15 is a screen shot of a companion device depicting a weight entryscreen, in accordance with one embodiment of the present specification;

FIG. 16 is a screen shot of a companion device depicting a well-beingentry screen, in accordance with one embodiment of the presentspecification;

FIG. 17A is an illustration depicting the distribution of the front andlateral T2-T12 dermatomes across a thorax and abdomen of a human body;

FIG. 17B is an illustration depicting the distribution of the posterioror back T2-T12 dermatomes across a trunk of the human body;

FIG. 17C is an illustration depicting the distribution of the anteriorand posterior C5-T1 dermatomes across a hand, arm and upper chestregions of a human body;

FIG. 17D is an illustration depicting the distribution of the C5-T1dermatomes across the ventral side of the hand and lower arm of thehuman body;

FIG. 17E is a flow chart listing the steps involved in one method ofidentifying a proper placement location for a percutaneouselectro-dermal patch on a front thoracic surface of a patient, inaccordance with one embodiment of the present specification;

FIG. 18A illustrates T6 stimulation using an neuro-stimulation device,in accordance with certain embodiments;

FIG. 18B illustrates T7 stimulation using an neuro-stimulation device,in accordance with certain embodiments;

FIG. 18C illustrates T6 and T7 stimulation using an neuro-stimulationdevice, in accordance with certain embodiments;

FIG. 19A illustrates C8 stimulation position of the ventral or front(palm) side of a user's hand using a percutaneous electro-dermal patch,in accordance with certain embodiments;

FIG. 19B illustrates C8 stimulation position of the dorsal or back sideof the user's hand using a percutaneous electro-dermal patch, inaccordance with certain embodiments;

FIG. 19C illustrates C8 and T1 stimulation position of the ventral sideof the user's lower arm or wrist regions using a percutaneouselectro-dermal patch, in accordance with certain embodiments;

FIG. 20A illustrates an embodiment of an neuro-stimulation device of thepresent specification wrapped around the edge of the user's hand forstimulating the C8 dermatome;

FIG. 20B illustrates another embodiment of an neuro-stimulation deviceof the present specification wrapped around the edge of the user's handfor stimulating the C8 dermatome;

FIG. 21A is a flow chart illustrating the steps involved in a method ofdetermining stimulation reaction thresholds and using a percutaneouselectro-dermal patch (PEDP) device to suppress appetite in a patient, invarious embodiments of the present specification;

FIG. 21B is a flow chart illustrating the steps involved in a method ofdetermining stimulation reaction thresholds and using a PEDP device tosuppress appetite in a patient, in various embodiments of the presentspecification;

FIG. 21C is a flow chart illustrating the steps involved in a method ofusing a neuro-stimulation device to suppress appetite in a patient, invarious embodiments of the present specification;

FIG. 22 is a flow chart illustrating the steps involved in a method ofusing a neuro-stimulation device to suppress appetite in a patient, invarious embodiments of the present specification;

FIG. 23 is a flow chart illustrating the steps involved in a method ofusing a neuro-stimulation device to suppress appetite in a patient, invarious embodiments of the present specification;

FIG. 24 is a flow chart illustrating the steps involved in a method ofusing a neuro-stimulation device to suppress appetite in a patient, invarious embodiments of the present specification;

FIG. 25 is a flow chart illustrating the steps involved in a method ofusing a neuro-stimulation device to suppress appetite in a patient, invarious embodiments of the present specification;

FIG. 26 is a flow chart illustrating the steps involved in methods ofusing a neuro-stimulation device to suppress appetite in a patient, invarious embodiments of the present specification;

FIG. 27 is a flow chart illustrating the steps involved in a using aneuro-stimulation device and a companion device, paired with a separatemonitoring device, to suppress appetite in a patient, in accordance withan embodiment of the present specification;

FIG. 28 is a flow chart illustrating steps involved in methods of usinga neuro-stimulation device to suppress appetite in a patient, in variousembodiments of the present specification;

FIG. 29A is a Visual Analogue Scale (VAS) questionnaire for assessing afeeling of hunger or appetite, in accordance with an embodiment;

FIG. 29B is a VAS questionnaire for assessing a feeling of fullness, inaccordance with an embodiment;

FIG. 29C is a VAS questionnaire for assessing a feeling of satiation, inaccordance with an embodiment;

FIG. 29D is a VAS questionnaire for assessing a feeling of satiety, inaccordance with an embodiment;

FIG. 30A is a graph illustrating pre-stimulation and post-stimulationhunger profiles of a first patient, in accordance with an embodiment;

FIG. 30B is a graph illustrating pre-stimulation and post-stimulationhunger profiles of a second patient, in accordance with an embodiment;

FIG. 30C is a graph illustrating pre-stimulation and post-stimulationhunger profiles of a third patient, in accordance with an embodiment;

FIG. 30D is a graph illustrating pre-stimulation and post-stimulationhunger profiles of a fourth patient, in accordance with an embodiment;

FIG. 30E is a graph illustrating pre-stimulation and post-stimulationhunger profiles of a fifth patient, in accordance with an embodiment;

FIG. 30F is a graph illustrating median AUC (Area Under the Curve)hunger scores for pre-stimulation, end-of-stimulation andpost-stimulation scenarios;

FIG. 30G is a graph illustrating pre-stimulation and post-stimulationhunger profiles over an extended period of time, in accordance with afirst embodiment;

FIG. 30H is a graph illustrating pre-stimulation and post-stimulationhunger profiles over an extended period of time, in accordance with asecond embodiment;

FIG. 30I is a graph illustrating hunger scores for pre-stimulation,end-of-stimulation and post-stimulation scenarios;

FIG. 31A is a graph illustrating pre-stimulation and post-stimulationsatiety profiles of a first patient, in accordance with an embodiment;

FIG. 31B is a graph illustrating pre-stimulation and post-stimulationsatiety profiles of a second patient, in accordance with an embodiment;

FIG. 31C is a graph illustrating pre-stimulation and post-stimulationsatiety profiles of a third patient, in accordance with an embodiment;

FIG. 31D is a graph illustrating pre-stimulation and post-stimulationsatiety profiles of a fourth patient, in accordance with an embodiment;

FIG. 31E is a graph illustrating pre-stimulation and post-stimulationsatiety profiles of a fifth patient, in accordance with an embodiment;

FIG. 31F is a graph illustrating median AUC (Area Under the Curve)satiety scores for pre-stimulation, end-of-stimulation andpost-stimulation scenarios;

FIG. 31G is a graph illustrating pre-stimulation and post-stimulationsatiety profiles over an extended period of time, in accordance with afirst embodiment;

FIG. 31H is a graph illustrating pre-stimulation and post-stimulationsatiety profiles over an extended period of time, in accordance with asecond embodiment;

FIG. 31I is a graph illustrating satiety scores for pre-stimulation,end-of-stimulation and post-stimulation scenarios;

FIG. 32A is a graph illustrating exercise scores of a sample of patientstreated with stimulation therapy, in accordance with an embodiment ofthe present specification;

FIG. 32B is a graph illustrating weights of a sample of patients treatedwith stimulation therapy, in accordance with an embodiment of thepresent specification;

FIG. 32C is a graph illustrating BMIs (Body Mass Index) of a sample ofpatients treated with stimulation therapy, in accordance with anembodiment of the present specification;

FIG. 32D is a graph illustrating appetite scores of a sample of patientstreated with stimulation therapy, in accordance with an embodiment ofthe present specification;

FIG. 32E is a graph illustrating dietary compliance scores of a sampleof patients treated with stimulation therapy, in accordance with anembodiment of the present specification;

FIG. 32F is a graph illustrating well-being scores of a sample ofpatients treated with stimulation therapy, in accordance with anembodiment of the present specification;

FIG. 33A is a bar graph illustrating mean cumulative changes of antralmotility indices for various stimulation sessions, in accordance with anembodiment; and

FIG. 33B is a bar graph illustrating maximum plasma endorphin levelsmeasured for various stimulation sessions, in accordance with anembodiment.

DETAILED DESCRIPTION

The present specification is directed toward systems and methods ofmodulating a patient's appetite, hunger, satiety level, satiation level,or fullness level by delivering electrical stimulation to apredetermined area of the user's anatomy in a manner that is convenient,easy to use, and amenable to increased patient compliance. The term“modulating” refers to any form of regulation, manipulation or controlto change a given variable from one state to another state. Moreparticularly, the present specification relates to electricalstimulation devices comprising low profile, wearable, disposablepercutaneous skin patches that are configured for placement and/orimplantation on a patient's front, lateral and back T2 to T12 and/orC5-T1 dermatomes, programmable and monitorable using a mobile handhelddevice, and programmed to stimulate, nerves located proximate to thefront, lateral and back T2 to T12 and/or C5-T1 dermatomes in a mannerthat enables modulation of a patient's appetite, hunger, satiety level,satiation level or fullness level, and that avoids nausea, dyspepsia andminimizes habituation. In some embodiments, a stimulation depth throughthe patient's skin ranges from 0.1 mm to 60 mm, with the stimulationelectrodes being placed percutaneously at a depth through the patient'sskin ranging from 0.1 mm to 60 mm. In various embodiments, a stimulationdepth through the patient's skin ranges from 0.1 mm to 30 mm, with thestimulation electrodes being placed percutaneously at a depth throughthe patient's skin ranging from 0.1 mm to 30 mm. The presentspecification further relates to a low profile, wearable, disposablepercutaneous skin patch that is capable of integrating with, and beingcontrolled by, a plurality of different hardware devices or softwareapplications depending on the type, extent, nature and scope of theappetite, hunger, satiety level, satiation level or fullness levelmodulation desired, including immediate, large weight loss or long termweight maintenance.

An electrical neuro-stimulation device, in the form of a percutaneouselectro-dermal patch (PEDP) is disclosed that, in various embodiments,is configured as a discrete, disposable and waterproof adhesive patch orpad for placement on a user's skin (while one or more electrodes laypercutaneously just underneath the user's skin), particularly on theregions encompassing the front, lateral and back T2-T12 dermatomesand/or C5-T1 dermatomes. In accordance with various aspects of thepresent specification, the PEDP device is configured to beself-implanted or self-administered by the user or implanted by aphysician or medical personnel. In various embodiments, the PEDP iswireless and incorporates flexible circuits and elastomeric overmolding,making the device waterproof and flexible enough to be able to mold tobody contours for greater comfort and permanent wearability. In someembodiments, the PEDP device also modulates ghrelin production.

In accordance with various aspects of the present specification, theresultant benefits of modulating appetite, hunger, satiety level,satiation level or fullness level include treating conditions associatedwith persons who are overweight or those with metabolic syndrome,treating obesity and T2DM prevention or management. In accordance withvarious aspects of the present specification, the neuro-stimulationdevice treats people having a BMI (Body Mass Index) of 25 or greater(overweight being 25-30, obese being 30 and above, and morbid obesitybeing above 35). In embodiments of the present specification, theneuro-stimulation device is wearable and can be controlled andprogrammed by the patient, allowing the patient to administer therapyand eliminating the need for frequent patient visits to a medicalprofessional. In embodiments, the neuro-stimulation device is designedto be placed on the front, lateral and back thoracic dermatomes and/orC5-T1 dermatomes of the patient.

In embodiments, the neuro-stimulation device is wirelessly coupled to acompanion device (e.g. smartphone, watch, glove, wristband or tablet)which can be used to program the neuro-stimulation device. In someembodiments, all therapy provided by the neuro-stimulation device iscoupled with a storage or recording (for keeping a log of the therapy)and patient compliance reminders. The benefits provided by having awearable neuro-stimulation device include, among others, greater patientindependence and improved patient compliance to stimulation protocols,with resultant increased dietary compliance and overall efficacy, andthe ability to modify stimulation parameters based on real-time feedbackprovided to the neuro-stimulation device by the patient and otherdevices. In some embodiments, the neuro-stimulation device is driven byan algorithm derived from patient input data and monitored data (e.g.exercise monitored by a separate device). Adjustments to the algorithm,and therefore stimulation, are made both manually by the patient andautomatically by the device itself or the companion device. In someembodiments, the neuro-stimulation device is driven by an algorithmderived from patient input data and monitored data (e.g. exercisemonitored by a separate device). In some embodiments, the algorithm isalso derived from monitored parameters, such as leptin (for ghrelinsuppression), glucagon-like peptide 1 (GLP-1), hemoglobin A1C, and bloodglucose levels (for diabetes treatment), lipids, and triglycerides.These parameters are measured at baseline and over time during treatmentand are used as inputs to titrate therapy. Adjustments to the algorithm,and therefore stimulation, are made either manually by the patient orautomatically by the neuro-stimulation device itself or the companiondevice or both. In accordance with some aspects of the presentspecification, a medical professional can flexibly program thepercutaneous electro-dermal patch and still direct the patient, onlyallowing the patient to adjust device parameters (for greater patientindependence) but within restricted bounds or predetermined parameters.

The present specification is directed towards multiple embodiments. Thefollowing disclosure is provided in order to enable a person havingordinary skill in the art to practice the invention. Language used inthis specification should not be interpreted as a general disavowal ofany one specific embodiment or used to limit the claims beyond themeaning of the terms used therein. The general principles defined hereinmay be applied to other embodiments and applications without departingfrom the spirit and scope of the invention. Also, the terminology andphraseology used is for the purpose of describing exemplary embodimentsand should not be considered limiting. Thus, the present invention is tobe accorded the widest scope encompassing numerous alternatives,modifications and equivalents consistent with the principles andfeatures disclosed. For purpose of clarity, details relating totechnical material that is known in the technical fields related to theinvention have not been described in detail so as not to unnecessarilyobscure the present invention.

It should be noted herein that any feature or component described inassociation with a specific embodiment may be used and implemented withany other embodiment unless clearly indicated otherwise.

For purposes of the present specification, the terms “trigger” and“triggering” do not necessarily imply immediately triggeringstimulation. “Trigger” and “triggering” are defined as initiating orstarting the execution of a protocol that will result in stimulationover a predefined period.

In the description and claims of the application, each of the words“comprise” “include” and “have”, and forms thereof, are not necessarilylimited to members in a list with which the words may be associated.

As used herein, the indefinite articles “a” and “an” mean “at least one”or “one or more” unless the context clearly dictates otherwise.

The terms “patient”, “individual”, “person”, and “user” are usedinterchangeably throughout this specification and refer to the personthat is receiving treatment or stimulation from the devices and methodsof the present specification.

The term “hunger” is defined as a physical sensation indicative of aperson's physical need for food and may be related to low levels ofglucose in the person's blood and/or concentrations of ghrelin and/orhunger-inducing gut hormones.

The term “appetite” is defined as a desire for food, possibly promptedby an emotional, psychological, and/or sensory reaction to the look,taste, or smell of food.

The term “satiation” is defined as a sensation of fullness that resultsin cessation of eating.

The term “fullness” is defined as a sensation of an adequate amount offood present in the stomach. It should be appreciated that the term“fullness” refers to a psychological or perceptive sensation by thepatient, which may be objectively measured using the scales describedherein. The term “physiological fullness” shall refer to a physicalmeasurement of the actual contents of a person's stomach.

The term “satiety” is defined as a sense of fullness that prolongs thetime between meals (the more satiety, the longer duration between twomeals). It is intended to refer to a patient's perception of a sense offullness that prolongs the time between meals.

The phrase “change in satiety” is defined as an alteration in thepatient's perception of gastric fullness or emptiness.

The term “dietary compliance” is defined as a patient's ability toadhere to a prescribed regimen of caloric intake, whether defined interms of total permissible calories or a type or amount of nutritionalintake, or some combination thereof, in order to achieve a targeteddaily, weekly, or monthly calorie consumption and/or a targeted type oramount of nutritional intake.

The phrase “weight maintenance” means adjusting an appetite or hungersuppression/decrease goal in order to maintain a certain amount ofweight loss that has already been achieved and to now avoid gainingweight. In some embodiments, weight loss maintenance entails engaging ina surgical procedure (such as various bariatric surgeries), applying thePEDP of the present specification and using appetite or hungersuppression/decrease in order to maintain the weight loss achieved bysurgery.

The term “microbiota” is defined as an ensemble of microorganisms thatreside in a previously established environment, such as the stomach orgastrointestinal system. The term “gut microbiota” or “gut flora is thename given to the microbiota living in a person's intestine.

The term “glycemic index (GI)” is defined as a number associated with aparticular type of food that indicates the food's effect on a person'sblood glucose (also called blood sugar) level. A value of 100 representsthe standard, an equivalent amount of pure glucose. The glycemic indexis calculated by determining the incremental area under the bloodglucose response curve of a specific portion of a test food expressed asa percent of the response to the same amount of carbohydrate from astandard food taken by the same subject.

The term “glycemic load (GL)” is defined as the glycemic indexmultiplied by grams of carbohydrate per serving size. GL is based on aspecific quantity and carbohydrate content of a test food and calculatedby multiplying the weighted mean of the dietary glycemic index by thepercentage of total energy from the test food. When the test foodcontains quantifiable carbohydrates, the GL=GI (%)×grams of carbohydrateper serving.

The term “epidermal layer” means the outer most layer of a person's skinand shall be construed to cover all variants of the word “epidermal”,including epidermis.

Throughout this specification, the term “power source” is used torepresent any energy providing device, including a lithium-ion battery,a betavoltaic battery, a solar cell, nickel-cadmium battery, a fuelcell, a mobile phone, or remote charging station.

The term “controller” is used to denote a processing unit configured tocontrol the initiation of stimulation, termination of stimulation, andtype and/or extent of stimulation and shall include the terms “controlunit”, “processing unit”, “microcontroller”, “microprocessor”, or“processor”.

The term “pulse generator” means a device configured to generateelectrical pulses in accordance with instructions from a controller. Itshould be appreciated that the pulse generator and controller can beintegrated into a single device or multiple devices.

The term “electrode” is used to refer to a conducting material that iscapable of receiving electrical pulses and communicating them to anothersurface.

The term “modulation” or “modulating” means any form of regulation,manipulation or control to change a given variable from one state toanother state.

Any increases or decreases in levels or rates are determined by thefollowing formula[(New Level or Rate)−(Old Level or Rate)]/(Old Level or Rate).

The phrase “at least one of x, y, and z” means that only one of x or yor z need to be true or present in order to satisfy that limitation.

The term “dermatome” refers to an area of skin that is primarilyinnervated and/or supplied by a specific spinal nerve.

The term “meridian” refers to low resistance fluid channels wherevarious chemical and physical transports take place and are individualpathways which exist among the subcutaneous tissues and serve aschannels for the flow of interstitial microscopic fluid throughout thebody.

Nerve Stimulation System

FIG. 1A is a block diagram illustration of a system 100 for stimulatingor modulating nerves and nerve endings in body tissues, in accordancewith an embodiment of the present specification. The system 100comprises a neuro-stimulation device 110 in data communication with acompanion device 105. In one embodiment, the neuro-stimulation device110 is in the form of a percutaneous electro-dermal patch (PEDP). Invarious embodiments, the companion device 105 is further capable ofbeing in data communication with a remote patient care facility, dataserver and/or patient care personnel. The companion device 105,comprising a computer readable medium and processor, can be any type ofcomputing and communication device, including a computer, server, mobilephone, gateway, laptop, desktop computer, netbook, personal dataassistant, remote control device or any other device capable ofaccessing a cellular, Internet, TCP/IP, Ethernet, Bluetooth, wired, orwireless network.

The neuro-stimulation device 110, in various embodiments, has a housing111 comprising a microprocessor or microcontroller 112 electronicallyconnected to a transceiver 114 to wirelessly communicate with thecompanion device 105, a pulse generator 116 to generate a plurality ofelectrical pulses for application through one or more electrodes 118 anda power management module 120, such as a lithium-ion battery, abetavoltaic battery, a solar cell, nickel-cadmium battery, or a fuelcell. In an embodiment, at least one electrode 118 is percutaneous. Inan embodiment, at least one electrode 118 is transcutaneous. In anembodiment, electrodes 118 are a combination of percutaneous andtranscutaneous. In an embodiment, electrodes 118 are percutaneouselectrodes that lay just underneath a user's skin. In some embodiments,the power management module 120 comprises a battery having a voltage ina range of 1.5 V to 4.5 V (for a single battery). The voltage depends onthe chemistry of the battery being used. In other embodiments, the powermanagement module 120 includes a plurality of batteries stacked inseries to increase the voltage supply, wherein per battery voltageranges from 1.5 V to 4.5 V. The power management module 120 has one ormore additional receptor slots 130 to enable snap on or clip onattachment of a disposable electronic assembly that includes a batteryfor providing additional backup charge to the neuro-stimulation device110.

Optionally, the housing 111 also comprises one or more actuators 122such as push buttons or switches to switch the device 110 on/off and toenable user control or settings of a plurality of stimulation therapyprotocols such as for toggling stimulation up or down, one or morevisual indicators 124, such as LEDs (Light Emitting Diodes), and one ormore tactile and audio indicators 126, such as a vibrator, buzzer orbeeper to provide feedback to a user, such as about the on/off state ofthe neuro-stimulation device 110, commencement or conclusion of therapy,battery charge/discharge, and/or malfunction of the neuro-stimulationdevice 110, among other information. In one embodiment, the one or moreactuators 122 includes a touch sensitive screen that enables (using anaccelerometer) the user to finger-tap to control and adjust stimulationtherapy protocols while the neuro-stimulation device 110 is still wornby the user. Still further embodiments may include (additionally oralternatively) control interfaces on the PEDP such as, but not limitedto, a slider on the surface of the PEDP, an infrared interface whereincommunication between the PEDP 110 and the companion device 105 isachieved by transmission of infrared radiation, a magnetic interfacewherein an external magnet or electro-magnet activates a reed switch orGMR (giant magnetoresistance) device or sensor positioned on the PEDP110, or an audible (speaker) command input interface. It should also beappreciated that, in one embodiment, the PEDP comprises no such on/offactuators or stimulation toggling actuators and is entirely controlledby an external device, as described below.

In various embodiments, the housing 111 is sealed so that it iswaterproof or water-resistant. In some embodiments, the housing 111 ishermetically sealed to be airtight. In various embodiments, the housing111 is molded from polymeric materials such as, but not limited to,polyolefins, PET (Polyethylene Terephthalate), polyurethanes,polynorbornenes, polyethers, polyacrylates, polyamides (Polyether blockamide also referred to as Pebax®), polysiloxanes, polyether amides,polyether esters, trans-polyisoprenes, polymethyl methacrylates (PMMA),cross-linked trans-polyoctylenes, cross-linked polyethylenes,cross-linked polyisoprenes, cross-linked polycyclooctenes,inorganic-organic hybrid polymers, co-polymer blends with polyethyleneand Kraton®, styrene-butadiene co-polymers, urethane-butadieneco-polymers, polycaprolactone or oligo caprolactone co-polymers,polylactic acid (PLLA) or polylactide (PL/DLA) co-polymers,PLLA-polyglycolic acid (PGA) co-polymers, and photocrosslinkablepolymers. In some embodiments, the housing 111 is of transparentpolymeric material to allow visibility of the contained electroniccomponents and circuitry.

In various embodiments, the microprocessor 112 is in electroniccommunication with one or more sensors 135 to generate datarepresentative of various physiological parameters of an individual,such as the individual's heart rate, pulse rate, beat-to-beat heartvariability, EKG or ECG, respiration rate, skin temperature, core bodytemperature, heat flow off the body, galvanic skin response or GSR, EMG,EEG, EOG, blood pressure, body fat, hydration level, activity level,oxygen consumption, glucose or blood sugar level, body position,pressure on muscles or bones, and/or UV radiation exposure andabsorption. In certain cases, the data representative of the variousphysiological parameters are the signal or signals themselves generatedby the one or more sensors 135 and in certain other cases the data iscalculated by the microprocessor 112 based on the signal or signalsgenerated by the one or more sensors 135. Methods for generating datarepresentative of various physiological parameters and sensors to beused therefor are well known to persons of ordinary skill in the art.

Table 1 provides several examples of well-known parameters and thesensor used to measure the parameter. The types of data listed in Table1 are intended to be examples of the types of data that can be generatedby the one or more sensors 135. It is to be understood that other typesof data relating to other parameters can be generated by theneuro-stimulation device 110 without departing from the scope of thepresent specification. It is further understood that the sensors may belocated in the housing 111, as shown in FIG. 1A, or remotely positionedfrom the housing 111 and configured to be electronic communication, viathe wireless transceiver 114, with the microcontroller 112.

TABLE 1 Parameter Sensor Heart Rate/Pulse Rate EKG (2 Electrodes)/BVP(LED Emitter and Optical Sensor) Beat-to-Beat Variability EKG (2Electrodes) EKG Skin Surface Potential EKG (3-10 Electrodes) RespirationRate Chest Volume Change (Strain Gauge) Skin Temperature SurfaceTemperature Probe (Thermistors) Core Temperature Esophageal or RectalProbe (Thermistors) Heat Flow Heat Flux (Thermopile) Galvanic SkinResponse Skin Conductance (2 Electrodes) EMG Skin Surface Potential EMG(3 Electrodes) EEG Skin Surface Potential EEG (Multiple Electrodes) EOGEye Movement Thin Film Piezoelectric Sensors Blood Pressure ElectronicSphygmomanometer Body Fat Body Impedance (2 Active Electrodes) ActivityAccelerometer Oxygen Consumption Oxygen Uptake (Electro-chemical)Glucose Level Electro-chemical sensors, Optical techniques, Aqueoustechniques (tears, saliva, and sweat), and Iontophoresis techniques.Body Position Mercury Switch Array, Accelerometer Muscle Pressure ThinFilm Piezoelectric Sensors UV Radiation UV Sensitive Photo Cells Bloodoxygen saturation Pulse oximeter

The microprocessor 112 is programmed to summarize and analyze the datarepresentative of the physiological parameters of the individual. Forexample, the microprocessor 112 can be programmed to calculate anaverage, minimum or maximum heart rate or respiration rate over adefined period of time, such as ten minutes. The neuro-stimulationdevice 110 is also able to derive information relating to theindividual's physiological state based on the data representative of oneor more physiological parameters. The microprocessor 112 is programmedto derive such information using known methods based on the datarepresentative of one or more physiological parameters. Table 2 providesexamples of the type of information that can be derived, and indicatessome of the types of data that can be used therefor.

TABLE 2 Derived Information Data Used Activity Heart rate, pulse rate,respiration rate, heat flow, activity, level oxygen consumption BasalHeart rate, pulse rate, respiration rate, heat flow, activity, metabolicoxygen consumption, glucose level rate Basal Skin temperature, coretemperature temperature Calories Heart rate, pulse rate, respirationrate, heat flow, activity, burned oxygen consumption Maximum EKG, heartrate, pulse rate, respiration rate, heat flow, oxygen blood pressure,activity, oxygen consumption consumption rate Relaxation EKG,beat-to-beat variability, heart rate, pulse rate, Level respirationrate, skin temperature, heat flow, galvanic skin response, EMG, EEG,blood pressure, activity, oxygen consumption Sleep onset/ Beat-to-beatvariability, heart rate, pulse rate, respiration wake rate, skintemperature, core temperature, heat flow, galvanic skin response, EMG,EEG, EOG, blood pressure, oxygen consumption Stress level EKG,beat-to-beat variability, heart rate, pulse rate, respiration rate, skintemperature, heat flow, galvanic skin response, EMG, EEG, bloodpressure, activity, oxygen consumption

Additionally, the neuro-stimulation device 110 may also generate dataindicative of various contextual parameters relating to the environmentsurrounding the individual. For example, the neuro-stimulation device110 can generate data representative of the air quality, soundlevel/quality, light quality or ambient temperature near the individual,or the global positioning of the individual. The neuro-stimulationdevice 110 may include one or more sensors for generating signals inresponse to contextual characteristics relating to the environmentsurrounding the individual, the signals ultimately being used togenerate the type of data described above. Such sensors are well known,as are methods for generating contextual parametric data such as airquality, sound level/quality, ambient temperature and globalpositioning.

In one embodiment, the neuro-stimulation device 110 includes at leastone or a combination of the following three sensors 135:

1) an impedance or bio-impedance sensor to determine electrodeintegrity, i.e. whether the electrode is functioning properly ordamaged, to detect and confirm contact integrity of the one or moreelectrodes 118 with tissues to be stimulated, or to estimate body fat orBody Mass Index (BMI) and accordingly modify or manage stimulationtherapy. In another embodiment, a first impedance or bio-impedancesensor is used to detect and confirm contact integrity of the one ormore electrodes 118 with tissues to be stimulated and a second impedanceor bio-impedance sensor is used to estimate body fat or Body Mass Index(BMI). In embodiments the impedance or bio-impedance sensor, ondetermination of successful contact integrity of electrodes withtissues, and therefore confirmation that the PEDP device is worn by theuser, switches the PEDP device ‘on’ for therapy;

2) an accelerometer or inclinometer to monitor user activity such aswalking, running, exercises, distance covered, sleep detection andmonitoring, sensing user input to the neuro-stimulation device 110,and/or

3) a neural activity monitor to detect presence of neural activity aswell as an amount of neural activity (firing rate).

In one embodiment, the neuro-stimulation device 110 only includes one ora combination of the following three sensors 135, and no other sensors:

1) an impedance or bio-impedance sensor to determine electrodeintegrity, i.e. whether the electrode is functioning properly ordamaged, to detect and confirm contact integrity of the one or moreelectrodes 118 with tissues to be stimulated, or to estimate body fat orBody Mass Index (BMI) and accordingly modify or manage stimulationtherapy. In another embodiment, a first impedance or bio-impedancesensor is used to detect and confirm contact integrity of the one ormore electrodes 118 with tissues to be stimulated and a second impedanceor bio-impedance sensor is used to estimate body fat or Body Mass Index(BMI). In embodiments, the impedance or bio-impedance sensor ondetermination of successful contact integrity of electrodes withtissues, and therefore ascertaining that the PEDP device is worn by theuser, switches the PEDP device ‘on’ for therapy,

2) an accelerometer or inclinometer to monitor user activity such aswalking, running, exercises, distance covered, sleep detection andmonitoring, sensing user input to the neuro-stimulation device 110,

3) a neural activity monitor to detect presence of neural activity aswell as an amount of neural activity (firing rate). With respect toconfirming contact integrity, it should be appreciated that, in oneembodiment, sufficient contact integrity of the one or more electrodes118 is defined in terms of achieving a predefined amount of electrodeimpedance with the patient's epidermal layer, such as in the range of200 to 1000 ohms, as measured by the impedance sensor.

The neural sensor is used to generate a plurality of feedback such as,but not limited to, an indication that the neuro-stimulation device 110is placed in the right location or area, an indication that theneuro-stimulation device 110 is increasing neural-activity in line with,and in accordance with, a stimulation protocol or an indication that theneural response rate is too slow or insufficient and, therefore, thestimulation protocol needs to be modified. Such plurality of feedbackgenerated by the neural sensor is provided to the user through a HealthManagement software application running on the user's hand-heldcomputing device such as a smartphone, PDA, tablet that, in variousembodiments, functions as the companion device 105. In some embodiments,the neural sensor connects to at least one of the one or morestimulation electrodes 118 while in some alternate embodiments, theneural sensor connects to at least one additional sensing electrode inaddition to the one or more stimulation electrodes 118. In someembodiments, the neuro-stimulation device 110 also includes a glucosesensor to monitor the user's blood glucose level.

In some embodiments, at least a portion of the electrodes 118 areremovably connectable to the housing 111. In one embodiment, at leastone of the electrodes 118 is configured to be partially positioned inthe housing 111 and extend outward. In another embodiment, at least oneof the electrodes 118 is configured to be a snap-on electrode where theelectrode 118 is removably connectable to an exterior surface of thehousing 111. This allows for the electrode 118 to be removed andreplaced with a new electrode 118, thereby reusing the electrical dermalpatch device 110 with a new electrode and minimizing the cost ofelectrodes that fail after just a few days of use.

FIG. 1B is a block diagram illustration of a system 141 for stimulatingor modulating nerves and nerve endings in body tissues, in accordancewith another embodiment of the present specification. In someembodiments, referring to FIG. 1B, the neuro-stimulation device (PEDP)140 includes a microcontroller 142, wireless transceiver 144, a powermanagement module 150, such as a lithium-ion battery, a betavoltaicbattery, a solar cell, nickel-cadmium battery, or a fuel cell, a pulsegenerator 146, and at least one electrode 148, and includes no otherphysical inputs or sensors on the PEDP 140 itself. The remaining inputsare on the companion device 105 and are actuated through the wirelesscoupling of the companion device 105 and PEDP 140.

In an embodiment, at least one electrode 148 is percutaneous. In anembodiment, at least one electrode 148 is transcutaneous. In anembodiment, electrodes 148 are a combination of percutaneous andtranscutaneous. In an embodiment, electrodes 148 are percutaneouselectrodes that lay just underneath a user's skin.

In some embodiments, rather than including a physical on/off switch, thePEDP 140 depicted in FIG. 1B is always using at least a minimum amountof power such that an ‘off’ state refers to a low power state. While nostimulation is being provided, there is, at a minimum, a periodic‘wake-up’ of the PEDP 140 to check for communication from the companiondevice 105. The ‘wake-up’ places the device in an ‘on’ state and, insome embodiments, includes no stimulation wherein the PEDP 140 runsdiagnostics for reporting to the companion device 105. Therefore, whilein the ‘off’ state, the PEDP 140 is constantly using a very low amountof power, is not providing stimulation, and is either awaiting a signalfrom the companion device or is performing diagnostics or othernon-stimulation activities requiring very little power. In someembodiments, the energy usage is less than 5 μA average current or inthe range of 0.1 μA to 5 μA average current while in the ‘off’ state andgreater than 10 μA average current while in the ‘on’ state. In someembodiments, the energy usage is at least 1 μA greater while in the ‘on’state than while in the ‘off’ state. Once the PEDP 140 receives a signalfrom the companion device 105 to initiate stimulation, it enters the‘on’ state and uses an amount of energy associated with the level ofstimulation. In another embodiment, the PEDP 140 uses no energy while inan ‘off’ state and must be awakened, or switched to an ‘on’ state, by asignal from the companion device.

FIG. 1C is a block diagram illustration of a system 161 for stimulatingor modulating nerves and nerve endings in body tissues, in accordancewith yet another embodiment of the present specification. In someembodiments, referring to FIG. 1C, the neuro-stimulation device (PEDP)160 includes a microcontroller 162, wireless transceiver 164, a powermanagement module 170, such as a lithium-ion battery, a betavoltaicbattery, a solar cell, nickel-cadmium battery, or a fuel cell, a pulsegenerator 166, one electrode 168, an optional single actuator 172 toturn the PEDP 160 on or off, one sensor 175 for sensing a physiologicalparameter of the patient, and includes no other physical inputs on thePEDP 160 itself. In one embodiment, the sensor 175 is a neural sensor.The remaining inputs are on the companion device 105 and are actuatedthrough the wireless coupling of the companion device 105 and PEDP 160.

In accordance with various aspects of the present specification, eachcomponent (power management module, microprocessor or microcontroller,pulse generator, transceiver, and one or more electrodes) of thepercutaneous electro-dermal patch may be positioned in a separatehousing, in a separate device, or otherwise physically remote from eachother. For example, as described with reference to FIG. 1A, theneuro-stimulation device 110 comprises a power management module 120,microprocessor or microcontroller 112, pulse generator 116, transceiver114, and one or more electrodes 118 in a housing 111.

However, in a first alternative embodiment as shown in FIG. 1D, theneuro-stimulation device 180 comprises a transceiver 182 having anantenna 184 for receiving electrical pulse signals 186 and an electrode183. A housing 181 may be positioned around the transceiver 182 andoptionally at least one electrode 183 or a substrate carrier may be usedto support a low-profile transceiver and/or electrode circuit withoutany additional housing structure. In this embodiment, an external device185 comprises the power source, controller, and pulse generator adaptedto generate a plurality of electrical pulses, as described earlier withreference to FIGS. 1A through 1C. The external device 185 may be awatch, mobile phone, a sensor pod configured to attach to the patientusing a strap or band, or other wearable device. The external device 185wirelessly transmits the electrical pulses 186 to the transceiver 182which, in turn, transmits the electrical pulses to the electrode 183and, thereafter, to the patient.

In a second alternative embodiment, as shown in FIG. 1E, the PEDP device190 comprises a transceiver 182 having an antenna 184 for receivingsignals 196, a pulse generator 187, and an electrode 183. A housing 191may be positioned around the transceiver 182, pulse generator 187, andoptionally at least one electrode 183. In this embodiment, an externaldevice 192 comprises the power source and controller adapted to generatean electrical signal, power signal, or data signal 196 that iswirelessly transmitted to transceiver 182 and, in turn, to the pulsegenerator 187 and used by the pulse generator 187 to generate aplurality of electrical pulses. The external device 192 may be a watch,mobile phone, a sensor pod configured to attach to the patient using astrap or band, or other wearable device. The electrical pulses arecommunicated to the electrode 183 and, thereafter, to the patient.

In a third alternative embodiment, as shown in FIG. 1F, the PEDP device195 comprises a transceiver 182 having an antenna 184 for receivingpower signals 197, a microprocessor or microcontroller 193, a pulsegenerator 187, and an electrode 183. A housing 194 may be positionedaround the transceiver 182, microcontroller 193, pulse generator 187,and optionally at least one electrode 183. In this embodiment, anexternal device 198 comprises a power source and transceiver adapted togenerate the power signal 197 that is wirelessly transmitted to thetransceiver 182 of the PEDP device 195 and, in turn, to themicrocontroller 193 and pulse generator 187 which generates a pluralityof electrical pulses. The external device 198 may be a watch, mobilephone, a sensor pod configured to attach to the patient using a strap orband, or other wearable device. The electrical pulses are communicatedto the electrode 183 and, thereafter, to the patient.

In a fourth alternative embodiment, each of the power source,controller, pulse generator, transceiver, and optionally at least oneelectrode are combined altogether in a single housing.

In a fifth alternative embodiment, the controller, pulse generator,and/or transceiver are combined together in a first housing while theelectrode and power source are in a disposable second housing, therebyallowing the electrode and the power source to be disposed of whenexhausted. Accordingly, the controller, pulse generator, and/ortransceiver could be reused and connected to a replacement electrode andpower source, yielding a refreshed device.

It should be appreciated that each of the above embodiments can beimplemented without a transceiver, replacing the wireless communicationwith a wired connection between the external device and theelectro-dermal patch. It should also be appreciated that, for eachembodiment, signal processing to determine data indicative of aphysiological condition can be done at the sensor level, i.e. in theimpedance or other sensor, at the controller level in the PEDP device,or at the external device level using a mobile application software orother program.

Percutaneous Electro-Dermal Patch (PEDP) Device Configurations

In accordance with an aspect of the present specification, theneuro-stimulation device 110 is configured as a wearable and disposablepercutaneous skin patch that is adhesively attached to the user's skin.In one embodiment, the entire assembly is disposed of once the batterydepletes. In accordance with an aspect of the present specification, theneuro-stimulation device 110 is configured to be worn for prolongedusage, such as for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14 days or up to 3 months continuously or any increment therein, andremoved solely for the purpose of recharging and/or replacing theelectrodes. The adhesive of the patch is preferably biocompatible toprevent skin irritation due to prolonged usage of the patch. Loctitemanufactured by Henkel, is a non-limiting example of a medical orbiocompatible adhesive. The adhesive of the pads provides sufficientattachment integrity of the PEDP to the user's skin. In variousembodiments, the PEDP has an average minimum ‘peel strength’ in a rangeof 1.3 to 1.7 Newton and preferably 1.5 Newton on living skin. Personsof ordinary skill in the art would appreciate that ‘peel strength’ isthe force required to remove or peel off the PEDP, having adhesive pads,from the user's skin and is a measure of the attachment integrity of thePEDP. ‘Peel strength’ is typically quantified by pulling the device froma flexible end or edge at an angle of 90 degrees from the skin surfaceat a peel rate that ranges from 100 to 500 mm/minute. In alternateembodiments, placement of the neuro-stimulation device 110 isaccomplished using a band, strap or a belt (for example, at the user'sarm or wrist regions). It should be appreciated that the term “adhered”is intended to encompass all forms of achieving device-to-skin contact,including adhesives, bands, straps, or belts.

Referring back to FIG. 1A, in accordance with some embodiments, the oneor more electrodes 118 are placed or inserted percutaneously up to adepth, ranging from 0.1 mm to 30 mm, in the skin and enable theneuro-stimulation device 110 to provide electrical stimulation therapyto a user. In various embodiments, a stimulation depth through thepatient's skin ranges from 0.1 mm to 30 mm.

For percutaneous electrical stimulation, in an embodiment, the presentspecification employs a first electrode configured as a transcutaneouselectrode pad for placing on the user's skin surface and a secondelectrode configured as a percutaneous electrode. In another embodiment,both the first and the second electrodes are configured as percutaneouselectrodes. In various embodiments, the percutaneous electrode is a finewire that is inserted to a depth into the user's skin to stimulate deepmusculature and nerves along with other tissues. The wire issubstantially coated with an electrical insulator except for a distalend, which remains uncovered to create an electrode. In variousembodiments, the length of the second electrode, that is thepercutaneous electrode, ranges from 0.1 mm to 60 mm and preferably from0.1 mm to 30 mm, or any increment therein. In various embodiments, thedepth of insertion of the percutaneous electrodes ranges from 0.1 mm to30 mm, at an angle of insertion ranging from 10 degrees to 90 degrees(with reference to the dermal layer), or any increment therein, todeliver stimulation through the skin, wherein the stimulated area rangesfrom 0.1 mm to 30 mm (with reference to the dermal layer), or anyincrement therein. In some embodiments, the percutaneous electrode isinserted into the skin to a depth of up to 10 mm.

Optionally, in embodiments where two or more electrodes are configuredas percutaneous electrodes, the two or more percutaneous electrodes mayoptionally be implanted at the same depths and/or the same angles ofinsertion, independently of each other, to deliver a desiredstimulation.

It should be appreciated that in embodiments where two or moreelectrodes are configured as percutaneous electrodes, the two or morepercutaneous electrodes may optionally be implanted at different depthsand/or at different angles of insertion, independently of each other, todeliver a desired stimulation. For example, a first electrode may beimplanted at a depth of 0.2 mm while the second electrode may beimplanted at a depth of 4 mm. In another example, the first electrodemay be inserted at an angle of 90 degrees and implanted at a depth of 2mm while the second electrode may be inserted at an angle of 15 degreesand implanted at a depth of 4 mm.

Optionally, in embodiments where two or more electrodes are configuredas percutaneous electrodes, the two or more percutaneous electrodes mayoptionally be implanted at different depths and/or the same angles ofinsertion, independently of each other, to deliver a desiredstimulation.

Optionally, in embodiments where two or more electrodes are configuredas percutaneous electrodes, the two or more percutaneous electrodes mayoptionally be implanted at the same depths and/or different angles ofinsertion, independently of each other, to deliver a desiredstimulation.

In accordance with various aspects of the present specification, thePEDP device is configured to be self-implanted or self-administered bythe user or implanted by a physician or medical personnel.

In a first embodiment, the PEDP device is self-implanted orself-administered by the patient. In such an embodiment, the user placesa PEDP device on his skin at an appropriate site or location whereby thePEDP device includes a deployable retractable needle positioned on thebottom surface of the device, which is in contact with the user's skin.When deployed, the needle punctures the user's skin and implants anelectrically conductive lumen underneath the skin. The needle is thenretracted. FIG. 1G is a flowchart illustrating a plurality of steps of amethod of self-implantation of the PEDP by a user, in accordance with anembodiment. At step 105 g, the user places the PEDP on the skin at anappropriate site or location for stimulation. Selection oridentification of the appropriate site is described in greater detailbelow. The user then, at step 110 g, deploys a needle positioned at thebottom surface (touching the user's skin) of the PEDP, by eitheractuating a button on the PEDP or using a GUI based button or icon on acompanion device, such as the user's smartphone. When deployed, theneedle punctures and penetrates the user's skin up to an appropriatedepth, such as 0.1 mm to 30 mm, and at a desired angle of insertionranging from 10 to 90 degrees (as described with reference to FIG. 2B inthis specification). At step 115 g, the deployed or inserted needledeposits, underneath the skin, a catheter or lumen that is electricallyconductive and malleable and capable of delivering stimulation. Once thecatheter or lumen is deposited, the needle is retracted, at step 120 g,leaving the catheter or lumen behind. In some embodiments, the needle isautomatically retracted. In other embodiments, the needle may beretracted using a button or GUI-based button or icon. In someembodiments, the needle may only be retracted when an adequateimplantation is confirmed by the device or companion device.

In a second embodiment of the present specification, referring back toFIG. 1A, the PEDP device includes one or more electrodes 118 configuredas an array of micro-needles that enable a patient-friendly intradermalstimulation delivery solution that can be self-implanted and positionedby the user. FIG. 1H shows an array of micro-needles 199 mounted on abase 138. The micro-needles 199, in some embodiments, are positionedusing springs for insertion into the patient's skin. The array ofmicro-needle electrodes 199 penetrate the skin barrier and deliverstimulation with reduced tissue damage, reduced pain, and reduced or nobleeding. In some embodiments, the depth of insertion of penetration ofthe micro-needle electrodes 199 ranges from 0.1 mm to 30 mm. In someembodiments, the depth of insertion or penetration of the micro-needleelectrodes 199 ranges from 0.1 mm to 4 mm.

In a third embodiment, the PEDP device of the present specification isimplanted by a physician or medical personnel. FIG. 2C is a perspectiveview of a percutaneous electrode insertion system 230 utilized by aphysician to implant one or more percutaneous electrodes underneath thepatient's skin. The system 230 comprises a housing 232 with a mountingsurface 235 adapted for application to the skin of the patient, inaccordance with some embodiments. The mounting surface 235 is defined bya plane and has a hollow needle 238 protruding therefrom. In variousembodiments, the needle 238 is surrounded by springs that are utilizedto deploy a percutaneous electrode (such as the electrode 211 of FIG.2A), inserted through the hollow needle 238, automatically at a desiredangle of insertion.

FIG. 2A shows a neuro-stimulation device 210 configured to providepercutaneous electrical stimulation therapy, in accordance with someembodiments. The device 210 includes an electrode pad or skin patch (notvisible) for placing on the user's skin surface and a percutaneouselectrode 211 in the form of an insulated fine wire 215 extending from abottom surface of the housing 213. A distal end 216 of the insulatedfine wire is bared or “stripped” of insulation to create an electrode.The housing 213 includes the microcontroller, pulse generator, wirelesstransceiver, and power management module of the system described withreference to FIGS. 1A through 1C.

In various embodiments, a depth of insertion of the percutaneouselectrode 211, into the user's skin, is governed by an angle at whichthe percutaneous electrode 211 enters the user's epidermal layer. FIG.2B illustrates the percutaneous electrode 211 entering the user'sepidermal layer 220 at an angle 225 of insertion (with reference to theepidermal layer 220). In various embodiments, the angle 225 of insertionranges from 10 degrees, corresponding to a shallow insertion scenario,to 90 degrees, corresponding to a most protruding scenario of insertionof the percutaneous electrode 211.

Optionally, in various embodiments, the neuro-stimulation device 210comprises a retractable needle coupled to the bottom surface of thehousing 213. In embodiments where the user self-implants the device 210,the device 210 is positioned on the user's skin and the retractableneedle is deployed to penetrate the user's skin to a desired depth andat a desired angle of insertion and deposit a conductive catheter orlumen underneath the user's skin. The needle is thereafter retractedleaving the catheter or lumen behind. In some embodiments, the device210 comprises an actuator, such as a button, which when triggered by theuser causes the retractable needle to be deployed. In additional oralternative embodiments, the retractable needle is deployable byactuating a GUI based icon or button the user's smartphone thatfunctions as a companion device.

In some embodiments, all of the components of neuro-stimulation device210 are positioned in a single patch such that neuro-stimulation device210 has a substantially flat profile. The lower profile ofneuro-stimulation device 210 facilitates patient comfort. In variousembodiments, the neuro-stimulation device 210, has a width w of 4 inchesor less, a length 1 of 8 inches or less, and a height h of 1.5 inches,and preferably 1 inch or less and still preferably 0.35 inches or less.In various embodiments, the neuro-stimulation device 210 has a weightranging from 5 grams to 250 grams. In various embodiments, theneuro-stimulation device 210 has a weight of 145 grams or less. Invarious embodiments, these dimensions include the percutaneous electrodeor micro-needle array portions. In various embodiments, these dimensionsdo not include the percutaneous electrode or micro-needle arrayportions.

In various embodiments, the dimensions and/or form factor of thepercutaneous electro-dermal patch device of the present specificationhas any one or a combination of the following attributes: asubstantially linear profile, a width of 4 inches or less, a length of 8inches or less and a height of 1 inch or less; a volume in a range of0.25 inches³ to 10 inches³; a weight in a range of 5 grams to 250 grams;a physical aspect ratio of width to thickness in a range of 1:1 to 6:1;a footprint of the PEDP device in a range of 3.5 inches² (1:1 aspectratio) to 6 inches² (6:1 aspect ratio); an electrical aspect ratio in arange of 1:1 to 1.5:1.

It should be appreciated that, while different physical configurationsmay exist for the percutaneous electrical dermal patch, it is importantthat the device deliver enough electrical stimulation in a reasonablysized patch structure, namely one that is not so large that it would beuncomfortable to wear.

In various embodiments, the neuro-stimulation device 210 has an ingressprotection rating (IPX) of at least IPX7, allowing the patient to takeshowers and swim for at least 30 minutes while the neuro-stimulationdevice 210 is positioned on the body without water damage to theneuro-stimulation device 210. In some embodiments, the adhesive portion(of the percutaneous electro-dermal patch) is surrounded along theperimeter with a closed cell foam to prevent water ingress to theadhesive and adhesion reduction in a long shower and/or a 30 minuteswim. In various alternate embodiments, the PEDP device 210 has aningress protection rating (IP) ranging from IP3 to IP5 and preferably awaterproof rating of IP4 (that is, protection from water splashing fromany direction for 5 minutes) per IEC standard 60529. Theneuro-stimulation device 210 is composed of a flexible, rubber orsilicone material with sufficient structural strength to remain on thebody once positioned while still flexible enough to be peeled back byits edges. The neuro-stimulation device 210 is storable when not in use.In other embodiments, the neuro-stimulation device 210 has an ingressprotection rating (IPX) of at least IPX1, IPX2, IPX3, IPX4, IPX5, orIPX6, as known to persons of ordinary skill in the art.

In one embodiment, the neuro-stimulation device 210 includes no visibleor tactile user interface and all communication with theneuro-stimulation device 210 is achieved wirelessly using a companiondevice as described further below.

In some embodiments, the neuro-stimulation device 210 includes adisposable battery which provides operating power for at least 90 daysof usage. In one embodiment, the neuro-stimulation device electroniccircuitry, in combination with the electrodes, is used to sense skinplacement and to turn therapy on and off automatically as furtherdescribed below. In one embodiment, the neuro-stimulation deviceelectronic core and adhesive pad with electrodes are all combined in oneflat component configured to provide therapy for at least 3 months. Inan alternate embodiment, the neuro-stimulation device electronic core islocated within a housing separate from the pad and, in some embodiments,is easily replaceable by the patient or a medical professional.

FIG. 3A illustrates a side view of a neuro-stimulation PEDP device inaccordance with one embodiment. The neuro-stimulation device (PEDPdevice) 300 has all electronics 302, power 301, a power transfermechanism 303, such as a coil, and electrode 304 captured within asingle unit structure. The PEDP device 300 contains at least oneelectrode 304, in the form of a very fine wire that passes through thecutaneous tissue (skin) to reach the dermatome. The wire is completelycoated with an electrical insulator except for the distal end where itis open to create an electrode. This portion is designed to be insertedinto or near the dermatome of interest.

The PEDP device 300, aside from at least one percutaneous electrode, isintended to be placed on, and adhered to, the skin over a dermatome ofinterest. The device 300 can have different shapes and sizes fordifferent body types. Placement can be accomplished via a biocompatibleadhesive on its surface, 305, a band, a belt, or other such fixturingmethods. The proper location of the electrode 304 may be determined by asensing mechanism. This sensing mechanism can be feedback from thepatient, an electronic sensing mechanism (e.g., biopotential amplifierwith analog filtering), or both. Once the proper location is found, thepatient can be tattooed to mark the spot for future device placements.

Optionally, in various embodiments, the PEDP device 300 comprises aretractable needle coupled to the bottom surface 305. In embodimentswhere the user self-implants the device 300, the device 300 ispositioned on the user's skin and the retractable needle is deployed topenetrate the user's skin to a desired depth and at a desired angle ofinsertion and deposit a conductive catheter or lumen underneath theuser's skin. The needle is thereafter retracted leaving the catheter orlumen behind. In some embodiments, the device 300 comprises an actuator,such as a button, which when triggered by the user causes theretractable needle to be deployed. In additional or alternativeembodiments, the retractable needle is deployable by actuating a GUIbased icon or button the user's smartphone that functions as a companiondevice.

FIG. 3B illustrates another embodiment for a neuro-stimulation PEDPdevice whereby electrodes are fully implanted. The target dermatome(s)are stimulated through a small structure 315 that has a plurality ofanodes and a plurality of cathodes and is placed in the subcutaneousregion 316 of a patient's body 317 proximate the target dermatome(s).This structure 315 also has a receiving mechanism to receive power fromoutside the patient's body 317. Power is transferred to structure 315from the PEDP device 310 which contains a battery 311, electronics 312,a power transfer mechanism 313, such as a coil. The PEDP device 310 isplaced with its bottom surface 314 in close proximity to saidsubcutaneous region 316 to enable transfer of power from power transfermechanism 313 to structure 315.

Optionally, in various embodiments, the PEDP device 310 comprises aretractable needle coupled to the bottom surface 314. In embodimentswhere the user self-implants the device 310, the device 310 ispositioned on the user's skin and the retractable needle is deployed topenetrate the user's skin to a desired depth and at a desired angle ofinsertion and deposit a conductive catheter or lumen underneath theuser's skin. The needle is thereafter retracted leaving the catheter orlumen behind. In some embodiments, the device 310 comprises an actuator,such as a button, which when triggered by the user causes theretractable needle to be deployed. In additional or alternativeembodiments, the retractable needle is deployable by actuating a GUIbased icon or button the user's smartphone that functions as a companiondevice.

FIG. 3C illustrates another embodiment for a neuro-stimulation PEDPdevice whereby the electrodes 325 are not part of the main devicehousing. The target dermatome(s) are stimulated through these electrodes325, which are operably connected to the PEDP device 320 via a cable324. The cable 324 can either be permanently connected to the device 320or detachable. The electrodes can be either percutaneous or acombination of cutaneous and percutaneous. It should be understood thatother portions of the device 320 could be detachable as well. Forexample, the unit could be constructed such that the power source 321and electrodes 325 are both detachable. This would make the electronics322 a reusable element of the device 320 while the power source 321 andelectrodes 325 can be disposable. Other such configurations can beenvisioned. Optionally, the device 320 also includes a power transfermechanism, such as a coil. A bottom surface 323 of the device includesan adhesive for securing the device 320 to a skin surface of a patient.

Optionally, in various embodiments, the PEDP device 320 comprises aretractable needle coupled to the bottom surface 323. In embodimentswhere the user self-implants the device 320, the device 320 ispositioned on the user's skin and the retractable needle is deployed topenetrate the user's skin to a desired depth and at a desired angle ofinsertion and deposit a conductive catheter or lumen underneath theuser's skin. The needle is thereafter retracted leaving the catheter orlumen behind. In some embodiments, the device 320 comprises an actuator,such as a button, which when triggered by the user causes theretractable needle to be deployed. In additional or alternativeembodiments, the retractable needle is deployable by actuating a GUIbased icon or button the user's smartphone that functions as a companiondevice.

FIG. 3D is another embodiment for a PEDP device 330 whereby there are noelectrodes disposed on the surface of the device and only onepercutaneous element 333 that extends outward from the surface of thedevice. The device 330 contains a battery 331, electronics 332 and,optionally, a power transfer mechanism. This embodiment allows for aplurality of electrodes, for example in the form of an array ofmicro-needles, to be on the percutaneous element 333. A bottom surface334 of the device includes an adhesive for securing the device 330 to askin surface of a patient.

Optionally, in various embodiments, the PEDP device 330 comprises aretractable needle coupled to the bottom surface 334. In embodimentswhere the user self-implants the device 330, the device 330 ispositioned on the user's skin and the retractable needle is deployed topenetrate the user's skin to a desired depth and at a desired angle ofinsertion and deposit a conductive catheter or lumen underneath theuser's skin. The needle is thereafter retracted leaving the catheter orlumen behind. In some embodiments, the device 330 comprises an actuator,such as a button, which when triggered by the user causes theretractable needle to be deployed. In additional or alternativeembodiments, the retractable needle is deployable by actuating a GUIbased icon or button the user's smartphone that functions as a companiondevice.

FIG. 3E is an embodiment of the percutaneous element 333 of FIG. 3D. Theelement 333 has four electrodes 341 connected to four pads 345 viaconductors 342. The element substrate 343 can be made from a flexiblematerial such as Kapton® (polyimide film) or other such material, andthe electrodes 341 and traces can be made of gold, platinum, etc. Aninsulate material such as polyimide or parylene can be used to preventshort circuiting of the electrode conductors in tissue.

FIG. 4 is a block diagram of a mobile electronics platform 400 that maybe employed with the devices of the present specification. System 400may be included in, for example, a mobile computing node such as acellular phone, smartphone, tablet, Ultrabook®, notebook, laptop,personal digital assistant, and mobile processor based platform.However, in other embodiments portions thereof may be included in theelectronics of the devices of FIGS. 3A-3E (e.g., leaving out one of thetwo cores, the keyboard, and the like).

Shown in FIG. 4 is a multiprocessor system 400 that includes a firstprocessing element 470 and a second processing element 480. While twoprocessing elements 470 and 480 are shown, it is to be understood thatan embodiment of system 400 may also include only one such processingelement. System 400 is illustrated as a point-to-point interconnectsystem, wherein the first processing element 470 and second processingelement 480 are coupled via a point-to-point interconnect 450. It shouldbe understood that any or all of the interconnects illustrated may beimplemented as a multi-drop bus rather than point-to-point interconnect.As shown, each of processing elements 470 and 480 may be multicoreprocessors, including first and second processor cores (i.e., processorcores 474 a and 474 b and processor cores 484 a and 484 b). Such cores474 a, 474 b, 484 a, 484 b may be configured to execute instruction codein a manner similar to methods discussed herein.

Each processing element 470, 480 may include at least one shared cache.The shared cache may store data (e.g., instructions) that are utilizedby one or more components of the processor, such as the cores 474 a, 474b and 484 a, 484 b, respectively. For example, the shared cache maylocally cache data stored in a memory 432, 434 for faster access bycomponents of the processor. In one or more embodiments, the sharedcache may include one or more mid-level caches, such as level 2 (L2),level 3 (L3), level 4 (L4), or other levels of cache, a last level cache(LLC), and/or combinations thereof.

While shown with only two processing elements 470, 480, it is to beunderstood that the scope of the present specification is not solimited. In other embodiments, one or more additional processingelements may be present in a given processor. Alternatively, one or moreof processing elements 470, 480 may be an element other than aprocessor, such as an accelerator or a field programmable gate array.For example, additional processing element(s) may include additionalprocessors(s) that are the same as a first processor 470, additionalprocessor(s) that are heterogeneous or asymmetric to first processor470, accelerators (such as, e.g., graphics accelerators or digitalsignal processing (DSP) units), field programmable gate arrays, or anyother processing element. There can be a variety of differences betweenthe processing elements 470, 480 in terms of a spectrum of metrics ofmerit including architectural, micro-architectural, thermal, powerconsumption characteristics, and the like. These differences mayeffectively manifest themselves as asymmetry and heterogeneity amongstthe processing elements 470, 480. For at least one embodiment, thevarious processing elements 470, 480 may reside in the same die package.

First processing element 470 may further include memory controller logic(MC) 472 and point-to-point (P-P) interfaces 476 and 478. Similarly,second processing element 480 may include a MC 482 and P-P interfaces486 and 488. MC's 472 and 482 couple the processors to respectivememories, namely a memory 432 and a memory 434, which may be portions ofmain memory locally attached to the respective processors. While MClogic 472 and 482 is illustrated as integrated into the processingelements 470, 480, for alternative embodiments the MC logic may bediscreet logic outside the processing elements 470, 480 rather thanintegrated therein.

First processing element 470 and second processing element 480 may becoupled to an I/O subsystem 490 via P-P interfaces 476, 486 via P-Pinterconnects 462, 404, respectively. As shown, I/O subsystem 490includes P-P interfaces 494 and 498. Furthermore, I/O subsystem 490includes an interface 492 to couple I/O subsystem 490 with a highperformance graphics engine 438. In one embodiment, a bus may be used tocouple graphics engine 438 to I/O subsystem 490. Alternately, apoint-to-point interconnect 439 may couple these components.

In turn, I/O subsystem 490 may be coupled to a first bus 410 via aninterface 496. In one embodiment, first bus 410 may be a PeripheralComponent Interconnect (PCI) bus, or a bus such as a PCI Express bus oranother third generation I/O interconnect bus, although the scope of thepresent invention is not so limited.

As shown, various I/O devices 414, 424 may be coupled to first bus 410,along with a bus bridge 418 which may couple first bus 410 to a secondbus 420. In one embodiment, second bus 420 may be a low pin count (LPC)bus. Various devices may be coupled to second bus 420 including, forexample, a keyboard/mouse 422, communication device(s) 426 (which may inturn be in communication with a computer network), and a data storageunit 428 such as a disk drive or other mass storage device which mayinclude code 430, in one embodiment. The code 430 may includeinstructions for performing embodiments of one or more of the methodsdescribed above. Further, an audio I/O 424 may be coupled to second bus420.

Note that other embodiments are contemplated. For example, instead ofthe point-to-point architecture shown, a system may implement amulti-drop bus or another such communication topology. Also, theelements of FIG. 4 may alternatively be partitioned using more or fewerintegrated chips than shown in the FIG. 4.

FIG. 5A is another embodiment of a PEDP device 500, wherein there are noactive electronics incorporated. Instead, an antenna 505 is connected toa simple passive rectifier circuit 502 to convert an RF signal 511 toenergy that is delivered to the electrodes 503 and 504. The antenna 505can be of various designs, such as a dipole antenna, inverted-F antenna,fractal antenna, or other such antenna that can efficiently receive thetransmitted RF power. An external wireless device 510 transmits the RFsignal 511 to the PEDP device 500. It should be appreciated thatwireless energy, in the form of electromagnetic energy, RF energy,ultrasound energy, or any combination thereof, is transferred from theexternal wireless device 510 (such as a smartphone, for example) to thePEDP device 500. An embodiment can use a half-wave rectifier, afull-wave rectifier, or any other passive rectifier circuits known inthe art, for the passive rectifier circuit. An embodiment can have oneantenna 505 or an additional second antenna 506 to account for RF signalpolarization. The electrodes 503, 504 can be percutaneous and/or skinsurface electrodes. An embodiment would contain sufficient electronicintelligence to avoid unintended stimulation from another externalwireless device, whether that be another patient controller or someother wireless device; e.g., airport security scanner, etc. Suchintelligence can be in the form of reading a specific data packetencoded in the RF transmission by means of modulation, such as amplitudemodulation, frequency shift keying modulation, or other suchconventional techniques.

An embodiment for an external wireless device 510 is a battery poweredportable device. An embodiment for the external wireless device can be asmartphone or any other commercially-available mobile electronicsplatform (such as that shown in FIG. 4). An embodiment can include anattachment 512 to a smartphone or commercially-available mobileelectronics platform which includes one or more of the following: anantenna, an RF signal generator circuit, an RF communication circuit,and an additional portable power source (e.g., battery). An embodimentfor the external wireless device can be portable, thereby incorporatinga portable power source. An embodiment for the external wireless devicecan be non-portable, thereby not requiring a portable power source andable to rely on the use of AC mains (connection to electrical wallsocket). An embodiment includes the ability to encode data in the RFtransmission to enable pairing to a desired PEDP device only.

FIG. 5B is another embodiment of a PEDP device that receives wirelessenergy for stimulation, and has elements of FIGS. 3B and 5A combined.More specifically, the PEDP device 5505 has the electrodes, antenna, andrectifier circuit fully implanted. The target dermatome(s) arestimulated through this small structure that has a plurality of anodesand a plurality of cathodes and is placed in the subcutaneous region5506 of patient's body 5507 proximate the target dermatome(s). Wirelessenergy 5501, in the form of electromagnetic energy, RF energy,ultrasound energy, or any combination thereof, is transferred from anexternal wireless device 5500 with embodiments as described in FIG. 5A.

Companion Device/Control

Referring back to FIG. 1A, the neuro-stimulation device 110 is in datacommunication with and controlled by the companion device 105 inaccordance with an aspect of the present specification. The companiondevice 105 is further capable of being in data communication with aremote patient care facility and/or patient care personnel. Thecompanion device 105 is in data communication with the neuro-stimulationdevice 110 through a direct link to drive therapy. In accordance with apreferred embodiment, the companion device 105 is a hand-held computingdevice such as a watch, wristband, smartphone, tablet, or PDA thatcontrols the neuro-stimulation device 110 through a wireless connection,such as Bluetooth, WiFi or any other private/public cellular or TCP/IPnetwork such as the Internet. In some embodiments, the companion deviceis physically separated from and external to the PEDP, hence referred toas a separate or external device. In some embodiments, the companiondevice may be a wearable activity monitor that tracks heart rates,movement, and other physiological data. In some embodiments, the PEDPmay be integrated into a wearable activity monitor and communicate withan external device, such as a smartphone, that is executing a softwareapplication in data communication with the wearable activity monitor.

The companion device 105 is configured to monitor and record (‘learn’) apatient's appetite patterns and monitor and record, learn, and modifythe stimulation parameters of the stimulation protocols delivered by theneuro-stimulation device 110. In some embodiments, all therapy providedby the neuro-stimulation device 110 is coupled with recording (keeping alog of the therapy) and patient compliance reminders provided by thecompanion device 105. FIG. 6A shows the neuro-stimulation device 610 ofthe present specification, configured as a percutaneous skin patch andplaced at a lateral thoracic dermatome, in accordance with anembodiment, and being wirelessly controlled by a smartphone 605, forexample.

With reference to FIG. 1A, in accordance with an aspect, the companiondevice 105, which is a hand-held computing device (such as a smartphone,tablet, PDA) in various embodiments, runs or implements a HealthManagement software application. The Health Management applicationactivates, deactivates and controls the neuro-stimulation device 110 toprovide a plurality of stimulation therapies or protocols in accordancewith various embodiments. In some embodiments, this is enabled bypairing or syncing the hand-held computing device (wirelessly or througha wired connection) with the neuro-stimulation device 110. In someembodiments, the Health Management application pairs or syncs andcontrols more than one neuro-stimulation device 110 worn by the user fortreating a combination of conditions.

In still further embodiments, the Health Management application iscapable of also communicating (via pairing or syncing) with a thirdparty device (including a third party application software on anexternal device), with physiological sensors, configured to be worn onthe human body, such as around the wrist, in order to monitor, acquire,record, and/or transmit the physiological data, to receive and integrateexercise and weight loss information, along with one or moreneuro-stimulation devices 110 of the present specification.

In some embodiments, multiple percutaneous electro-dermal patch (PEDP)devices 110 are networked together with a single companion device 105 toaggregate data feedback from the PEDP devices 110. The aggregated datais then used to modify stimulation parameters and develop more precisestimulation algorithms. In various embodiments, the companion device 105enables social networking with friends and family, provides voicerecognition and voice feedback, and includes anti-hacking dataprotection for HIPAA compliance. In some embodiments, the wirelessconnection (for pairing or syncing) is optionally compliant with HIPAAand other regulatory body requirements and laws relating to OUS (OutsideUnited States) countries for patient data privacy. In variousembodiments, the wireless connection is encrypted to prevent hacking ofthe device to retrieve patient data and/or inappropriately stimulate thepatient and/or destroy the device.

In various embodiments, as shown in FIG. 6B, using a companion device625, 635, 645, 655, 665 multiple PEDP users 620, 630, 640, 650, 660 cannetwork with one another and communicate regarding their therapy over ashared network connection 621, such as a cloud-based connection, whichcan lead to improved patient compliance to stimulation protocols, withresultant increased dietary compliance. For example, networked PEDPusers could share and exchange experiences, progress, dietary ideas, andsuccess stories. In some embodiments, networked exchanges areautomatically input into companion devices, resulting in changes totherapy provided by the PEDP devices. For example, in one embodiment,aggregated dosing data is used to reset baseline default dosing settingsto provide different dietary recommendations. Traditionally, small groupclinical studies are performed to obtain data used for creating dosingstrategies. By networking PEDP users through companion devices, largeramounts of aggregated user settings can be obtained automatically, forexample, via a cloud based connection, and used to automatically finetune dosing settings. In some embodiments, PEDP users have the ability,over a network connection, to share data among friends and family whoare also users. In some embodiments, PEDP users can be segmented intodiet clubs based on their connected friends and/or based on the type ofdiet they have chosen. Therefore, in various embodiments, users canconnect with friends and also connect into “groups” defined around thetype of diet plan, i.e. Atkins, Mediterranean, and intermittent fasting,they are following. Further, in some embodiments, users connected to agroup, for example, Weight Watchers, can receive “group therapy” supportin the form of input, as needed or at periodic intervals, from amoderator or therapist. In embodiments, the “groups” also enablecommunication between PEDP devices, between users, and between users anda moderator or therapist. Such interconnectivity among friends, groups,and moderators/therapists provides a larger support network for PEDPusers and promotes user compliance.

In some embodiments, a PEDP user network functions as a dosing settingsand dietary information exchange. For example, in an aggregate patientdata network, multiple different patients have a PEDP communicating witha personal companion device. FIG. 6C is a flow chart listing the stepsin one embodiment of a method of aggregating, organizing, and analyzingstimulation parameters and patient hunger, appetite, and well-beingscores for a plurality of patients, each having a PEDP device withlinked companion device connected to an aggregate patient network. Atstep 672, each patient connects to the aggregate patient network usingtheir companion device. At step 674, periodically, e.g. several times aday, once a day, 2-6 times a week, or any such increment, anonymizeddata regarding the patient's stimulation parameters including, but notlimited to, stimulation pulse width, pulse amplitude, pulse frequency,pulse shape, duty cycle, session duration, and session frequency,together with the patient's corresponding hunger, appetite, andwell-being scores (the hunger, appetite, and well-being scores beingcollectively referred to as patient status data), are transmitted to acentral server, or set of servers.

At the central server, at step 676, the anonymized data from multipleusers are organized into a collective database and analyzed todetermine 1) the stimulation parameters including, but not limited to,stimulation pulse width, pulse amplitude, pulse frequency, pulse shape,duty cycle, session duration, and session frequency, which typicallylead to sufficient appetite suppression without an unacceptabledecrement in well-being and 2) the stimulation parameters including, butnot limited to, stimulation pulse width, pulse amplitude, pulsefrequency, pulse shape, duty cycle, session duration, and sessionfrequency, which typically lead to sufficient appetite suppressionwithout an unacceptable decrement in well-being for specific demographicsectors. In some embodiments, patient status data such as the hunger andappetite scores are aggregated into a composite score, also referred toas a satiety score. In some embodiments, exercise scores reflective ofcalories expended are also factored into the composite or satiety score.The user can share her composite score (along with treatment orstimulation settings that led to the composite score) with friends andfamily via social networking, to illicit advice, encouragement andcompare progress with fellow dieters.

It should be appreciated that while in some embodiments data regardingthe patients' stimulation parameters is anonymized, in some embodimentsthe data may not be anonymized if the patients sign away theirrespective privacy rights.

In various embodiments, hunger and appetite scores across demographicprofiles are analyzed to determine what stimulation settings achieveoptimum appetite and hunger levels or scores for a given age, gender,BMI, ethnicity, weight loss goal, or bacterial microbiome profile. Thus,for a given user, once the optimum stimulation settings are identified,it is then determined how stimulation settings for the given user mustbe modified in order to match those optimum stimulation settings, and amodulation signal is transmitted in order to establish those new(optimum) stimulation settings.

In various embodiments, the PEDP device, and the electrical stimulationit delivers, is configurable and re-configurable for different therapiesand for different aspects within a specific therapy. For example,regarding weight loss and management, the patient and/or companiondevice can configure the PEDP to deliver electrical stimulation in aneffort to promote active weight loss in the patient and then, once atarget weight is achieved, reconfigure the PEDP to deliver electricalstimulation to maintain the patient at the target weight. This can beaccomplished via one or more applications downloaded to the companiondevice. FIG. 6D is a flow chart illustrating the steps involved in usingone or more downloadable applications to configure and reconfigurestimulation provided by a percutaneous electro-dermal patch (PEDP)device, in accordance with one embodiment of the present specification.At step 680, a patient obtains or has a PEDP implanted by a medicalprofessional. At step 681, the patient pairs a companion device with thePEDP and with a separate physiological monitoring device withphysiological sensors, configured to be worn on the human body, such asaround the wrist, in order to monitor, acquire, record, and/or transmitphysiological data to the companion device, wherein the companion deviceis adapted to create and modify stimulation parameters based on themonitored physiological data. At step 682, the patient then downloads,from an online marketplace, a first application designed to configurethe PEDP to achieve a first objective associated with a specifictherapy, for example, weight loss for weight management. The patientpositions the PEDP on his body at step 683. The first application, atstep 684, configures the PEDP for the first objective by establishingcertain baseline stimulation parameters designed to achieve said firstobjective and by titrating or fine-tuning said stimulation parametersbased on patient diary input into the companion device and/orphysiological data transmitted to the companion device by the separatemonitoring device. After the first objective has been achieved, at step685, the patient then downloads a second application, from an onlinemarketplace, designed to reconfigure the PEDP to achieve a secondobjective associated with the specific therapy, for example, maintainingweight for weight management.

In various embodiments, one or both of the first and second applicationsis available from the online marketplace for a fee. Additionally, boththe first and second applications may be separate and distinctapplications which reside on the companion device, are separatelyobtained by accessing the on-line application marketplace associatedwith the companion device, and are activated, and executed, by clickingon separate and distinct icons from the companion device's home screen.In another embodiment, the first application may be downloaded from theon-line application marketplace associated with the companion device andmay be activated, and executed, by clicking on separate and distincticons from the companion device's home screen while the secondapplication, and all subsequent applications responsible for modulatingthe PEDP's stimulation parameters, are downloaded by accessing amarketplace of such applications through the first application.Specifically, the first application provides a gateway to a database, orlibrary, of additional applications which may provide for differentstimulation parameters based on inputs, weights, and other criteria thatdiffer from the first application, or each other.

The second application, at step 686, then configures the PEDP for thesecond objective by establishing certain baseline stimulation parametersdesigned to achieve said second objective and by titrating orfine-tuning said stimulation parameters based on patient diary inputinto the companion device and/or physiological data transmitted to thecompanion device by the separate monitoring device. In one embodiment,for weight management, the stimulation parameters for the firstobjective (weight loss) are more focused on patient diary record ofwell-being and hunger as inputs to titrate therapy while the stimulationparameters for the second objective (weight maintenance) are morefocused on daily body weight as an input to titrate therapy. Whileweight management has been used to describe the method above formodifying therapy provided by the PEDP, in various embodiments, themethod of using one or more online applications to configure andreconfigure the stimulation parameters of the PEDP can be used on anycondition receptive to electrical stimulation therapy.

In various embodiments, the PEDP and companion device are open source toallow for the creation of applications for the devices designed to enacttherapy methods similar to the one described above. In anotherembodiment, a single master application downloadable to a companiondevice is responsible for controlling the PEDP and setting initialstimulation parameters. This master application may come with the PEDPupon initial purchase or may be separately purchasable or downloadablefor free from an online marketplace. In various embodiments, furthersoftware upgrades, such as in-application or “in-app” purchases, can beobtained, for a fee, within the master application and used to fine-tunetherapy. In various embodiments, such software upgrades include, forexample, new diet plans, new exercise plans, and improved fitnesstracking, among others. In various embodiments, these software upgradesare created by third parties or by the creator of the masterapplication. In some embodiments, new applications or software upgradesto a master application reconfigure the PEDP to provide electricalstimulation targeting different conditions. For example, in variousembodiments, applications or upgrades reconfigure baseline PEDPstimulation parameters to treat other conditions including, but notlimited to, dysmenorrhea, back pain, urinary incontinence, andperipheral neuropathy, including diabetic peripheral neuropathy. In someembodiments, the electrical components of the device are the same andthe patient uses a different, disposable electrode patch portion andrepositions the device on his or her body. These applications andupgrades modify the algorithms used by the companion device to changethe stimulation parameters for the PEDP to treat the differentconditions. For example, in one embodiment, a patient initially uses thePEDP for weight management in a method similar to that described above.She then downloads a fee based online application to the companiondevice which then reconfigures the PEDP stimulation to treat herdysmenorrhea. She can then use her initial application to return thePEDP back to weight management settings. She could continually downloadnew applications and upgrades and reconfigure the PEDP to treat aplurality of different conditions and go back and forth betweendifferent conditions. It would be preferred that, for the non-weightloss applications, such as urinary incontinence, back pain, dysmenorrheaand peripheral neuropathy, including diabetic peripheral neuropathy, acompletely different application be downloaded while for new ordifferent weight loss plans, it would be preferred to downloadadditional applications through the first downloaded weight lossapplication itself, thereby avoiding having multiple different anddistinct weight loss applications on the companion device's home screen.

Because the presently disclosed embodiments are directed to medicaltreatments, it is imperative that patient specific data, such as datarepresenting specific stimulation settings and patient status data, arestored, transmitted, and verified in a manner that is secure and subjectto authentication. In one embodiment, data transmissions between thePEDP, the companion device, and any remote server(s) are subject toverification and authentication, such as by using checksums, private andpublic keys, and other forms of verification known in the art. If, atany time, one or more of the data transmissions fail to be properlyverified or authenticated, any new or modulated stimulation settingsassociated with such data transmissions are discarded or otherwise setaside and only a previous stimulation setting associated with a fullyverified and/or authenticated complete set of data transmissions isused. Alternatively, the system may lock the use of any stimulationsetting until such data transmissions can be fully verified, along withany new or modulated stimulation settings associated therewith.

FIG. 6E is a flow chart illustrating the steps involved in a method of acompanion device verifying and/or authenticating data transmissionreceived from a remote server, in accordance with some embodiments ofthe present specification. At step 690, a patient obtains a percutaneouselectro-dermal patch (PEDP) device from a medical professional. Thepatient pairs a companion device with the PEDP and with a remote server,in a secure manner subject to verification and authentication, at step691. At step 692, the companion device receives a data transmissioncomprising new or modulated stimulation settings from the remote server.The companion device then checks if the data transmission is properlyverified and/or authenticated at step 693. In one embodiment, if thedata transmission is properly verified and/or authenticated, thecompanion device controls the PEDP to deliver electrical stimulationbased on the new or modulated stimulation settings at step 694. In oneembodiment, if the data transmission is not properly verified and/orauthenticated, the new or modulated stimulation settings are discardedor otherwise set aside and a previous stimulation setting associatedwith a fully verified and/or authenticated complete set of datatransmissions is used at step 695. In another embodiment, if the datatransmission is not properly verified and/or authenticated, thecompanion device locks the use of any stimulation setting until the datatransmission can be fully verified, along with any new or modulatedstimulation settings associated therewith at step 696.

In another embodiment, communications between a PEDP, companion deviceand any remote server(s) may comprise an indication, such as a packetheader, identifier, tag, or other representation, of whether thespecific PEDP involved in the data transmissions is a device that hasbeen sold subject to FDA regulatory approval or whether it is a devicethat has not been sold subject to FDA regulatory approval. Depending onsuch an identifier (indicative of government regulatory governance, orsome extent thereof), different data processing may occur. For example,if the companion device or remote server(s) determine the PEDP inquestion is subject to FDA approval (based on an identifier being storedin a memory within the PEDP), it may cause a different or higher levelof encryption, authentication, and/or verification to be applied to thestored data or to data transmissions. In one case, all datatransmissions to and from the PEDP, between the PEDP and companiondevice, and/or between the companion device and remote server(s) areencrypted, authenticated, and anonymized subject to verification. Inanother case, only data transmissions containing patient-specificstimulation settings or patient status data are encrypted,authenticated, and/or subject to verification while all other datatransmissions are not encrypted.

If, on the other hand, the companion device or remote server(s)determines the PEDP in question is not subject to FDA approval (based onan identifier being stored in a memory within the PEDP), it may cause alower level of encryption, authentication, and/or verification to beapplied to the stored data or to data transmissions relative to the FDAcase. In one embodiment, no data transmissions to and from the PEDP,between the PEDP and companion device, and/or between the companiondevice and remote server(s) are encrypted, authenticated, and subject toverification. In another case, only data transmissions containingpatient-specific stimulation settings or patient status data areauthenticated and/or subject to verification and no data transmissionsare encrypted.

FIG. 6F is a flow chart illustrating the steps involved in a method ofencrypting, authenticating, and/or verifying data transmissions betweena PEDP, companion device, and remote server based on FDA approval statusof the PEDP, in accordance with some embodiments of the presentspecification. At step 661, a patient obtains a percutaneouselectro-dermal patch (PEDP) device from a medical professional. Thepatient pairs a companion device with the PEDP and with a remote server,in a secure manner subject to verification and authentication, at step662. At step 663, the companion device and/or remote server determine ifthe PEDP is subject to FDA approval based on an indication (packetheader, identifier, tag) on the PEDP. In one embodiment, if it isdetermined that the PEDP is subject to FDA approval, then all datatransmissions to and from the PEDP, between the PEDP and companiondevice, and/or between the companion device and remote server areencrypted, authenticated, and subject to verification at step 664. Inanother embodiment, at step 666, if it is determined that the PEDP issubject to FDA approval, only data transmissions containingpatient-specific stimulation settings or patient status to and from thePEDP, between the PEDP and companion device, and/or between thecompanion device and remote server are encrypted, authenticated, and/orsubject to verification and all other data transmissions are notencrypted. In another embodiment, if it is determined that the PEDP isnot subject to FDA approval, then no data transmissions to and from thePEDP, between the PEDP and companion device, and/or between thecompanion device and remote server are encrypted, authenticated, andsubject to verification at step 667. In another embodiment, at step 669,if it is determined that the PEDP is not subject to FDA approval, onlydata transmissions containing patient-specific stimulation settings orpatient status to and from the PEDP, between the PEDP and companiondevice, and/or between the companion device and remote server areauthenticated and/or subject to verification and no data transmissionsare encrypted.

In accordance with an aspect of the present specification, patientstatus data and, if needed, stimulation setting, parameters andprotocols are transmitted to insurance companies to support medicaltreatments, such as bariatric surgeries, or other insurance claims, orfor other general insurance data needs. In some embodiments, such datatransmission may be subjected to encryption, authentication andverification as described at step 666.

The Health Management Application (hereinafter also referred to as‘HMA’) of the present specification comprises a plurality ofprogrammatic instructions and algorithms and implements a plurality ofGUIs (Graphical User Interface) to enable a plurality of functions,non-limiting examples of which are described henceforth.

Referring back to FIG. 1A, in various embodiments, the HMA enablesconfirming linkup to the neuro-stimulation device 110 and displayingbattery life of the neuro-stimulation device 110.

The HMA enables generating an audio and/or visual indicator on thehand-held computing device 105 indicating that a) the neuro-stimulationdevice 110 has been properly placed on and implanted within the user'sbody by, for example, confirming sufficient electrode and tissue contactor integrity, b) the one or more electrodes 118 is aged or compromised(ascertained by, for example, impedance measurements) and needs to bereplaced. In some embodiments, electrode and tissue contact integrityand electrode integrity, i.e. whether the electrode is functioningproperly or damaged, are checked through at least one impedance orbio-impedance sensor of the neuro-stimulation device 110. In otherembodiments, an acoustic sensor, capable of sensing specific acousticsignals unique to an area of the human body, is used to determine if theneuro-stimulation device 110 has been properly positioned on the user'sbody. In various embodiments, sufficient electrode and tissue contact orintegrity is defined as achieving electrode impedance in a range of 200ohms to 1000 ohms. In one embodiment, pulse amplitude is automaticallyadjusted by virtue of there being a constant current source (from one ormore batteries). A constant current source circuit automatically adjuststhe pulse to maintain a programmed amplitude in the event ofelectrode-tissue interface impedance changes. This automatic adjustmentmay be programmed to occur for voltages ranging from 0.1V to 500V.Accordingly, the pulse amplitude is automatically modulated in order tomaintain a constant current source.

The HMA also enables analyzing sensed neural activity prior to thecommencement of a stimulation therapy to assess and indicate to the userthat the neuro-stimulation device 110 has been placed at an appropriatelocation, such as the T2-T12 and/or C5-T1 dermatomes for eatingdisorders. In various embodiments, the accuracy or appropriateness ofthe neuro-stimulation device location is assessed through the neuralactivity monitor of the neuro-stimulation device 110. In variousembodiments, neural activity sensing or monitoring is accomplished byusing a sense amplifier circuit to measure neural activity and output arepresentative signal to the microcontroller or microprocessor of theneuro-stimulation device 110. The microcontroller algorithmicallyprocesses the data to determine if there is neural activity. In someembodiments, the sense amplifier circuit measures neural activitysignals directly using the same electrodes used for stimulation. Inother embodiments, the sense amplifier circuit measures neural activitysignals separately using different electrodes than those used forstimulation. In still other embodiments, the sense amplifier circuitmeasures neural activity signals using both the same electrodes used forstimulation and different electrodes than those used for stimulation. Invarious embodiments, the sense amplifier circuit incorporates a gain ina range of 1 to 100,000,000 and all values in between, and incorporatesa bandpass filter of 0.1 Hz to 10,000 Hz and all combinations inbetween. These functions are accomplished using conventional analogcircuitry known in the art, such as operational amplifier circuits andtransistor circuits. In one embodiment, a process used by themicroprocessor to process the sensed neural activity comprises countingthe number of events within a predetermined time period. In otherembodiments, the process is modified to add moving averages in the formof finite impulse response (FIR) or infinite impulse response (IIR)digital filters.

The HMA also enables analyzing sensed neural activity during astimulation therapy to assess effectiveness of the stimulation.Depending upon the effectiveness, the Health Management application mayautomatically recommend and/or implement adjustments or modifications toa plurality of stimulation parameters. In some embodiments, therecommended adjustments to the plurality of stimulation parameters mustbe accepted or authorized for implementation by at least one of the user(that is, the patient) and/or the remote patient care facility orpersonnel. In various embodiments, neural activity is sensed using asense amplifier circuit as described above.

The HMA enables the user to self-administer therapy, including theability to stimulate multiple times per day or per week, therebyaccelerating treatment effect and efficacy. In various embodiments, theself-administration is on-demand and is actuated via a button on thecompanion device 105 used to trigger the neuro-stimulation device 110.Triggering the neuro-stimulation device 110 is defined as triggering aprotocol that may result in stimulation over a predefined period anddoes not necessarily indicate electrical stimulation begins immediately.The companion device 105 and/or neuro-stimulation device 110 includepre-programmed restrictions which prevent the patient fromover-stimulating. In addition, the companion device 105 and/orneuro-stimulation device 110 include triggers which prompt the patientto stimulate based upon time of day, historical trends in appetite,caloric intake, and exercise data.

The HMA enables the user to input his current weight per day through aGUI screen and provides real-time or near real-time integration offeedback from patient parameters such as, but not limited to, exerciseand fitness, diet, hunger, appetite, and well-being, recorded in apatient daily diary, from the patient and obtaining real-time or nearreal-time integration of feedback, such as steps taken as an indicatorof calories burned, from other wearable devices, for example, a device,with physiological sensors, configured to be worn on the human body,such as around the wrist, in order to monitor, acquire, record, and/ortransmit the physiological data, allowing for frequent adjustability andcustomization of therapy as needed. The integration of feedback from thepatient and from other devices allows for modification of therapy, asneeded, to suppress appetite and treat conditions such as obesity,over-weight, and/or metabolic syndrome. In accordance with variousaspects of the present specification, the neuro-stimulation deviceenables treating people with BMI (Body Mass Index) of 25 or greater(overweight being 25-30, obese being 30 and above, with morbid obesitybeing above 35).

The HMA enables providing recording, storage and display of allstimulation parameters and other real-time inputs, such as diary andexercise monitoring, to provide the physician and patient real-timerecords and treatment profiles. The information stored includes acombination of inputs from the stimulation device and from other sourcesof information, for example, from a device, with physiological sensors,configured to be worn on the human body, such as around the wrist, inorder to monitor, acquire, record, and/or transmit the physiologicaldata.

The HMA enables presenting GUI screens to enable the user to provideinputs such as, but not limited to, eating information and activitiesinformation. In various embodiments, eating information comprisesstandard regular eating and meals profile or routine of the user such asthe number of meals per day typically consumed and the types and amountsof food eaten at each of the meals per day. The standard regular eatingand meals profile is typically input only once by the user as itrepresents the general eating habit of the user and is likely to bemodified by the user over long periods of time. In some embodiments, thestandard regular eating and meals profile is representative of astandard diet plan such as, but not limited to, Mediterranean,Intermittent Fasting, Jenny Craig, Weight Watchers, SlimFast and CustomPlan.

In various embodiments, eating information additionally or alternativelycomprises real time actual eating and meals profile of the user such asthe time of consumption of a meal in a day and the type and amount offood eaten at the meal. In other words, each time the user consumes ameal he (in real time) records the occurrence of the meal event, whichis automatically time stamped by the application, as well as the typeand amount of food eaten. If the meal being consumed and the type andamount of food are in line with the user's standard regular eatingprofile, he may simply select the meal and types and amounts of foodfrom the pre-stored eating profile of the user.

In accordance with an aspect of the present specification, the real timeeating and meals profile is utilized to calculate the actual amount ofcalories consumed by the user in a day. On the other hand, the standardregular eating and meals routine of the user is utilized to calculate aforecasted or expected amount of calories likely to be consumed by theuser in a day. A difference between the daily, weekly or monthlyexpected and actual calories consumption value may prompt a plurality ofrecommendations from the Health Management application to the user.

In accordance with some aspects of the present specification, it isadvantageous to also assess the quality of meal or diet consumed alongwith the amount of calories consumed as a result of the meal or diet ina day. In some embodiments, the quality of a meal or diet is determinedbased on a mix of macronutrients such as carbohydrates (also referred toas “carbs”), proteins and fats present in the meal or diet. Thus, theuser's standard diet plan may propose an acceptable ratio for eachmacronutrient. For example, the Zone Diet (by Barry Sears, PhD) proposesa meal of 40% carbs, 30% protein and 30% fats, the Atkins Diet proposesa meal of 5% carbs, 25% protein and 75% fats, while the Ketogenic Dietproposes a meal of 10% carbs, 45% protein and 45% fats. Thus, for a userwho is endeavoring to follow a standard diet plan or a custom diet plandesigned around a specific ratio of macronutrients, the expected ratioof macronutrients and the expected calories likely to be consumed in aday are known and pre-stored by the Health Management application.

In various embodiments, the actual or real time eating and meals profileof the user is indicative of the time of consumption of a meal in a dayas well as the type and amount of food eaten at the meal. The type andamount of food eaten enables calculating the calories consumed as wellas a ratio of macronutrients, that is, carbs, protein and fats consumed.It should be appreciated that while in some embodiments, the HealthManagement application calculates the ratio of all three macronutrients,(carbs, proteins and fats) consumed in a meal, in various alternateembodiments, an amount and effect of any one or two macronutrients maybe monitored and calculated. For example, in some embodiments, theHealth Management application is focused on monitoring and determiningthe effect of carbohydrates consumed compared to an acceptable amount ofcarbohydrates allowed based on the standard diet plan being followed bythe user.

Thus, in accordance with an aspect, carbohydrate containing foods arerated on a scale called the glycemic index (GI) and the glycemic indexis used to calculate a glycemic load (GL) associated with the foodconsumed. The GI ranks carbohydrate containing foods based on theireffect on blood sugar levels over a period of time. Carbohydratecontaining foods are compared with glucose or white bread as a referencefood, which is given a GI score of 100. The GI compares foods that havethe same amount of carbohydrate, gram for gram. Carbohydrates that breakdown quickly during digestion have a higher glycemic index (say, GI morethan 70). These high GI carbohydrates, such as a baked potato, releasetheir glucose into the blood quickly. Carbohydrates that break downslowly, such as oats, release glucose gradually into the bloodstream.They have low glycemic indexes (say, GI less than 55). The blood glucoseresponse is slower and flatter. Low GI foods prolong digestion due totheir slow break down and may help with satiety.

The glycemic index compares the potential of foods containing the sameamount of carbohydrate to raise blood glucose. However, the amount ofcarbohydrate consumed also affects blood glucose levels and insulinresponses. The glycemic load (GL) takes into account both the GI of thefood and the amount of carbohydrate in a portion or serving consumed. GLis based on the idea that a high GI food consumed in small quantitieswould give the same effect on blood glucose levels as larger quantitiesof a low GI food. GL is calculated by multiplying the GI by the amountof carbohydrates (in grams) in a serving of food.

Thus, in accordance with another aspect of the present specification,the real time eating and meals profile is utilized to calculate theratio of macronutrients, that is, carbs, proteins and fats, consumed ina day or at least the glycemic load (GL) associated with the mealsprofile. On the other hand, the standard regular eating and mealsroutine of the user is utilized to calculate a forecasted, allowed orexpected ratio of the macronutrients consumed by the user in a day or atleast the allowable glycemic load. A difference between the daily,weekly or monthly expected and actual macronutrient ratio or adifference between the daily, weekly or monthly expected and actualglycemic load may prompt a plurality of recommendations from the HealthManagement application to the user.

Activities information relates to how much and when a person movesaround and/or exercises during the day and utilizes both data input bythe user and data sensed by the one or more sensors 135. The data inputby the user may include details regarding the user's daily activities,for example the fact that the user worked at a desk from 9 a.m. to 5p.m. and then took an aerobics class from 6:30 p.m. to 7:30 p.m.Relevant data sensed by the sensors 135 may include heart rate, movementas sensed by an accelerometer, heat flow, respiration rate, caloriesburned, and galvanic skin response (GSR). Accordingly, calories burnedor spent (calories expenditure) maybe calculated in a variety ofmanners, including: the multiplication of the type of exercise input bythe user by the duration of exercise input by the user; sensed motionmultiplied by time of motion multiplied by a filter constant; and sensedheat flux multiplied by time multiplied by a filter constant or on thebasis of metabolic equivalents (METs). In some embodiments, the user'sRMR (Resting Metabolic Rate) or BMR (Basal Metabolic Rate) is alsocalculated to estimate the amount of calories consumed by the user whichis then used to calculate a daily caloric balance. As known to personsof ordinary skill in the art, RMR or BMR is the rate at which you burnenergy or calories when resting and is a function of at least the user'sage, gender, height and weight. This helps fulfill the basicrequirements of the body to function optimally.

The amount of calories actually consumed by the individual is comparedto the amount of calories expended or burned by the individual fordaily, weekly or monthly periods and is referred to hereinafter asenergy balance of the user. A positive or surplus energy balance isrepresentative of more actual calories consumed in comparison to thecalories expended and is considered to be indicative of a potentialweight gain scenario for the user over a period of time. A negativeenergy balance is representative of less actual calories consumed incomparison to the calories expended and is considered to be indicativeof a potential weight loss scenario for the user over a period of time.

Continuing with various non-limiting examples of the plurality offunctions of the HMA, in various embodiments the HMA also enablespresenting GUI screens to enable the user to record his hunger orappetite profile. Hunger or appetite profile includes data such as thetime of day when the user feels hungry and the intensity of hunger felt.In some embodiments, the intensity of hunger is recorded by the user byselecting from a scale of, for example, 1 to 5, where 1 is indicative oflight hunger and 5 is indicative of very high hunger intensity. Invarious embodiments, the hunger profile includes only those times whenthe user feels hungry but should ideally not consume a meal. This mayinclude, for example, times that do not match the user's standardregular eating and meals profile or routine.

The HMA further enables providing daily feedback from theneuro-stimulation device to the patient on dietary compliance, caloriesburned and displaying diet plans.

The HMA also enables receiving, processing and analyzing glucose datagenerated by a glucose sensor, included as one of the sensors 135, insome embodiments. In various embodiments, the glucose data is analyzedto detect conditions such as a hyperglycemic rush, resulting from, forexample, a large carbohydrate meal, and titrate stimulation to treat ormanage a condition where there is a surplus of insulin secretion thatmay trigger hunger in non-diabetic users.

The HMA enables generating and displaying a plurality of charts orgraphs representative of the user's standard regular eating and mealsprofile, actual eating and meals profile, energy balance information,weight trend including a rate of weight loss or gain, glucose data trendand hunger profile over a period of time such as daily, weekly ormonthly.

The HMA enables managing and generating prompts (audio, visual and/ortactile) with respect to a plurality of compliance aspects such as, butnot limited to: stimulation therapy compliance—prompts the user if theuser forgets to apply the neuro-stimulation device and/or disables arecommended duration or frequency of stimulation therapy; prompts theuser with respect to a stimulation protocol that a scheduled stimulationis going to begin in the next T minutes, 10 minutes for example, andpresenting the user with an option to disable the scheduled stimulationwhich if not disabled allows the scheduled stimulation to begin after Tminutes; dietary compliance or guidance—the user either selects apredefined standard dietary plan (from a drop down list of multiplepredefined dietary plans, such as but not limited to Mediterranean Zonediet, Atkins diet, or Jenny Craig) or inputs a customized plan as partof the standard regular eating and meals routine. The user also recordsdetails of the actual meals taken and time of meals. Audio, visualand/or tactile alert(s) may be generated, for example, if the user isnot in compliance with the selected dietary plan. The compliance promptsare intended to encourage patient compliance and, in some embodiments,include composite scores and displays for overall patient progress.

The HMA enables recommending and/or implementing modification tostimulation patterns or protocols when receiving an input from the userthat the user is encountering a feeling of nausea, dyspepsia, heartburn,or sensation at the stimulation site during and/or after stimulation.

The HMA further enables assessing stimulation habituation, nausea and/ordyspepsia scenarios in the user and accordingly modifying thestimulation patterns or protocols. In various embodiments, these eventsare input into the neuro-stimulation device or companion device by thepatient. For example, in one embodiment, the patient can input, via aGUI on one or both devices, nausea events, dyspepsia events or hungerevents. The microprocessor then algorithmically processes these eventsand accordingly modifies stimulation.

The HMA enables the remote patient care facility and/or patient carepersonnel to access (via cellular and/or private or public wired orwireless networks such as the Internet) a plurality of user's healthrelated information such as the user's hunger profile, standard eatingand meals profile, actual eating and meals profile, energy balance,weight trends, glucose data and stimulation induced nausea, dyspepsia,habituation events. In some embodiments, the Health Managementapplication periodically transmits the user's health related informationapart from enabling the remote patient care facility and/or patient carepersonnel to access such information in real time or on demand, ifrequired. In various embodiments, the user's authorization is needed toallow such access to the user's health related information.

The HMA also enables detecting removal of the neuro-stimulationdevice—the impedance or bio-impedance electrode enables the HealthManagement application to regularly or continuously monitor electrodeactivity. This allows the Health Management application to detectwhether the neuro-stimulation device has been removed or worn by theuser. This enables the neuro-stimulation device to stimulate only whenit is confirmed that the device is being worn by the user. In someembodiments, where the neuro-stimulation device is configured for use asa 24/7 wearable device, detection of removal of the neuro-stimulationdevice corresponds to missing of the user's health related information.However, in other embodiments, where the neuro-stimulation device isconfigured for use on as-needed or on-demand basis, any missing userhealth related information is treated as non-occurrence of anystimulation event.

The HMA also enables providing unique electrical stimulationcharacteristics and ‘footprints’, based on electrode design andstimulation parameters, allowing the patient to use a variety ofmethodologies for stimulation.

In still a further non-limiting example, the HMA enables providing aweight loss graph along with the patient's pictures corresponding tovarious milestones on the weight loss graph.

In still a further non-limiting example, the HMA enables; enablesbariatric surgeons, doctors, dieticians or medical personnel to tell newpatients about their medical practice.

In still a further non-limiting example, the HMA enables patients tokeep time intervals between meals and fluids. For example, the HMA maynotify users when enough time has passed after drinking to eat and viceversa.

In still further non-limiting examples, the HMA enables patients to viewtheir medical personnel and request an appointment with the office;enables setting of daily reminders for prescribed vitamins andsupplements; enables patients to pose queries to their dietician;enables communicating schedules of weight loss seminars and supportgroups, to the patients; enables medical personnel to communicatehealthy recipes with the patients to support their continued weight losssuccess; enables bariatric surgery patients to stay on track withreminders and a pre-populated checklist—Psych Eval, InsurancePre-approval, Physician Supervised Diet; enables medical personnel aswell as patients to journalize daily thoughts and progress notes;enables information exchange with third party applications; enablespatients to track their water intake along with food consumed; enablesautomatic tracking of calories, protein, fat and carbohydrates consumedby patients; enables scanning of barcodes of package food to allowpatients to see the nutritional information, and have it loggedautomatically to the feed consumed daily diary; enables physicians ormedical personnel to enter specific goals for their patients; enablesphysicians to share their patient status data, with approval from theirpatients, with the fellow practice/department physicians to solicitbetter recommendations for the patients; enables instilling weightmanagement habits in the patients since monitoring of food/caloriesintake leads to better dietary compliance; enables physicians,dieticians and other medical personnel to send out push notifications totheir patients to keep the patients engaged and motivated towards theirhealth goals.

It should be appreciated that in various embodiments, the user'splurality of health related information is utilized by the HealthManagement application to suggest and/or implement a plurality ofrecommendations comprising stimulation patterns or protocols, medication(such as an amount of insulin intake, for example), dietary and/oractivities plans. For example, if the user's actual calories consumptionis found to be higher than the expected calories consumption,consistently over a period of time, the Health Management applicationmay recommend any one or a combination of: a specific standard diet planto the user; a change from a first standard diet plan to a secondstandard diet plan or prescribe customization of an existing standarddiet plan that the user may be following; recommend or change anexisting stimulation protocol to suppress the user's appetite and/orsuggest to the user to increase his activity levels such as walking,exercising.

In some embodiments, the plurality of recommendations is auto-generatedby the Health Management application and presented to the user for hisauthorization for implementation. In some embodiments, the plurality ofrecommendations auto generated by the Health Management application arepresented to the remote patient care facility and/or personnel forauthorization or approval and thereafter either implemented or presentedagain to the user for a final authorization for implementation. In someembodiments, the Health Management application receives a plurality ofrecommendations prescribed by the remote patient care facility and/orpersonnel based on the user's plurality of health related information.

In various embodiments, the user is presented, on one or more GUIs, aplurality of recommendations, which are auto generated by the HealthManagement application as well as those received as prescriptions orrecommendations from the remote patient care facility or personnel, thereasons for each of the plurality of recommendations,authorizations/approvals or disapprovals against each of the pluralityof recommendations as received from the remote patient care facility orpersonnel, and annotations or notes from the remote patient carefacility or personnel describing reasons for approving or disapprovingeach of the plurality of recommendations that were generated by theHealth Management application. The user then reviews andauthorizes/approves or disapproves implementation of each of theplurality of recommendations. In some embodiments, however,authorizations to implement the plurality of recommendations may not berequired from the user and/or the remote patient care facility orpersonnel. For example, in one embodiment wherein the neuro-stimulationdevice is worn 24 hours per day, the number of stimulation sessions pera specified time period is automatically titrated up or down based onthe recommendations. In another embodiment, the duration of stimulationis automatically titrated up or down based on the recommendations. Inother embodiments, other stimulation parameters are changedautomatically based on the recommendations.

In various embodiments, the companion device includes a ‘diary’ for thepatient to input, track, record, and display patient parameters. FIG. 7is a screen shot of a companion device depicting a diary widget 705, inaccordance with one embodiment of the present specification. The diarywidget 705 includes icons enabling the patient to input and view entriesin the diary. The diary widget 705 includes a quick entry buttons icon706 which, when pressed, causes the companion device to display buttonsfor making diary entries. The diary widget 705 also includes a list viewof diary entries icon 707 which, when pressed, causes the companiondevice to display the diary in a list format. The diary widget 705 alsoincludes a calendar view of diary entries icon 708 which, when pressed,causes the companion device to display the diary in a calendar format.

FIG. 8 is a screen shot of a companion device depicting a list view ofdiary entries 805, in accordance with one embodiment of the presentspecification. The list view of diary entries 805 is accessed bypressing the list view of diary entries icon 707 as shown on FIG. 7. Invarious embodiments, the list view of diary entries 805 displays entriesinput by the patient for instances such as stimulation sessions 806 andpatient parameters, for example, hunger 807 and appetite 808. Thestimulation session entry 806 displays the time 816 of the entry anddetails 826 of the stimulation session. Each patient parameter entry807, 808 displays the time 817, 818 of the entry, the type of parameter837, 838, and a score with description 827, 828 associated with theentry. The list view of diary entries 805 also displays the date 803 andthe name of the diary 802 being viewed.

FIG. 9 is a screen shot of a companion device depicting a calendar viewof diary entries 905, in accordance with one embodiment of the presentspecification. The calendar view of diary entries 905 is accessed bypressing the calendar view of diary entries icon 708 as shown on FIG. 7.The calendar view of diary entries 905 displays the days 906 of themonth being viewed. Pressing on an individual day displays the diaryentries for that day as a list 907. The patient can scroll through thelist 907 to view entries. The calendar view of diary entries 905 alsodisplays the month and year 903 and the name of the diary 902 beingviewed.

FIG. 10 is a screen shot of a companion device depicting a quick entrybuttons view 1005, in accordance with one embodiment of the presentspecification. The quick entry buttons view 1005 is accessed by pressingthe quick entry buttons icon 706 as shown on FIG. 7. In one embodiment,the quick entry buttons view 1005 includes six quick entry buttons:appetite 1006, exercise 1007, hunger 1008, stim (that is, stimulation)sessions 1009, weight 1010, and well-being 1011. The quick entry buttonsdepicted in FIG. 10 are exemplary only and not intended to be limiting.In other embodiments, fewer or additional quick entry buttons areincluded on the quick entry buttons view. Pressing on any one of thequick entry buttons 1006, 1007, 1008, 1009, 1010, 1011 causes thecompanion device to display an entry screen for the chosen button. Thequick entry button view 1005 also displays the name of the diary 1002being viewed.

FIG. 11 is a screen shot of a companion device depicting an appetiteentry screen 1105, in accordance with one embodiment of the presentspecification. The appetite entry screen 1105 allows the user to enterthe type 1106 and item 1107 of patient parameter, in this case appetite,and a score 1108 associated with the parameter. The score 1108 has anumerical value 1109 and a description 1110 associated therewith to helpthe patient determine which score best fits the current parameter. Insome embodiments, for appetite, the description relates to how much thepatient ate compared to the amount recommended by the patient's diet. Insome embodiments, the score ranges from 1 to 5. The appetite entryscreen 1105 also displays the time and date 1103 the entry is beingentered and the name of the diary 1102. The patient can save the entryby pressing the disk icon 1101 or cancel the entry by pressing the Xicon 1104.

FIG. 12 is a screen shot of a companion device depicting an exerciseentry screen 1205, in accordance with one embodiment of the presentspecification. The exercise entry screen 1205 allows the user to enterthe type 1206 and item 1207 of patient parameter, in this case exercise,and a score 1208 associated with the parameter. The score 1208 has anumerical value 1209 and a description 1210 associated therewith to helpthe patient determine which score best fits the current parameter. Insome embodiments, for exercise, the description relates to how manysteps the patient took per day. In some embodiments, the score rangesfrom 1 to 5. The exercise entry screen 1205 also displays the time anddate 1203 the entry is being entered and the name of the diary 1202. Thepatient can save the entry by pressing the disk icon 1201 or cancel theentry by pressing the X icon 1204.

FIG. 13 is a screen shot of a companion device depicting a hunger entryscreen 1305, in accordance with one embodiment of the presentspecification. The hunger entry screen 1305 allows the user to enter thetype 1306 and item 1307 of patient parameter, in this case hunger, and ascore 1308 associated with the parameter. The score 1308 has a numericalvalue 1309 and a description 1310 associated therewith to help thepatient determine which score best fits the current parameter. In someembodiments, for hunger, the description relates to the level of hungerthe patient is experiencing. In some embodiments, the score ranges from1 to 5. The hunger entry screen 1305 also displays the time and date1303 the entry is being entered and the name of the diary 1302. Thepatient can save the entry by pressing the disk icon 1301 or cancel theentry by pressing the X icon 1304.

FIG. 14 is a screen shot of a companion device depicting a stimulationsession entry screen 1405, in accordance with one embodiment of thepresent specification. The stimulation session entry screen 1405 allowsthe user to enter the type 1406 and item 1407 of session, in this case astimulation session, and a level 1408 associated with the session. Thelevel 1408 has a numerical value 1409 and a description 1410 associatedtherewith to help the patient determine which level best represents whatwas applied during the current session. In some embodiments, forstimulation session, the description relates to how often stimulationwas delivered per day and for how long the stimulation was appliedduring each session. In some embodiments, the level ranges from 1 to 4.The stimulation session entry screen 1405 also displays the time anddate 1403 the entry is being entered and the name of the diary 1402. Thepatient can save the entry by pressing the disk icon 1401 or cancel theentry by pressing the X icon 1404.

FIG. 15 is a screen shot of a companion device depicting a weight entryscreen 1505, in accordance with one embodiment of the presentspecification. The weight entry screen 1505 allows the user to enter thetype 1506 and item 1507 of patient parameter, in this case weight, and aweight in pounds 1508 associated with the parameter. The weight entryscreen 1505 includes a numeric keypad 1509 for the patient to use toenter the weight. The weight entry screen 1505 also displays the timeand date 1503 the entry is being entered and the name of the diary 1502.The patient can save the entry by pressing the disk icon 1501 or cancelthe entry by pressing the X icon 1504.

FIG. 16 is a screen shot of a companion device depicting a well-beingentry screen 1605, in accordance with one embodiment of the presentspecification. The well-being entry screen 1605 allows the user to enterthe type 1606 and item 1607 of patient parameter, in this well-being,and a score 1608 associated with the parameter. The score 1608 has anumerical value 1609 and a description 1610 associated therewith to helpthe patient determine which score best fits the current parameter. Insome embodiments, for well-being, the description relates to a level ofnausea, dyspepsia and/or abdominal discomfort the patient isexperiencing. In some embodiments, the score ranges from 1 to 3. Thewell-being entry screen 1605 also displays the time and date 1603 theentry is being entered and the name of the diary 1602. The patient cansave the entry by pressing the disk icon 1601 or cancel the entry bypressing the X icon 1604.

It should be appreciated that the HMA incorporates GUIs that presentscales, surveys, or questionnaires designed to quantitatively assess oneor more of a person's appetite, hunger, level of satiety, level ofsatiation, level of fullness, level of well-being, level of nausea,feelings of pain, level of dyspepsia, perception of food, and changesthereto.

For example, SNAQ (Simplified Nutritional Appetite Questionnaire) is anappetite assessment tool that predicts weight loss. SNAQ includesquestions that rank, on a scale of 1 to 5, the strength of appetite,feelings of fullness after eating, taste of food and number of mealseaten each day. A SNAQ score of less than or equal to 14 predicts highlikelihood of at least 5% weight loss within six months. The GhrelinHunger Scale (G-scale) is a two dimensional scale wherein a first scaleof 1 to 7 on the y-axis is used to assess the feeling of hunger/fullnessand a second scale of 1 to 7 on the x-axis is used to assess the timeelapsed since a last meal (breakfast, lunch, snack, or dinner).

In general, each such scale is a form of a visual analog scale (VAS). AVAS is question-based assessment mechanism, where a visual measure isassociated with each question and where answering the question requiresselecting a quantifiable position within that visual measure, indicativeof a particular level or degree. The scale is typically composed oflines (of varying length) with words anchored at each end, describingthe extremes (that is, ‘I am not hungry at all’ on the left to ‘I havenever been more hungry’ on the right). Patients are asked to make a markacross the line corresponding to their feelings. Quantification of themeasurement is done by measuring the distance from the left end of theline to the mark. In some embodiments, VAS may be used to assesssensations of pain (due to stimulation, for example), hunger, appetite,satiation, fullness, satiety, overall quality of life, degree of nausea,degree of well-being, degree of dyspepsia, perception of food, foodaversions, and perceptions of dietary compliance.

FIG. 29A illustrates a VAS questionnaire 2905 for assessing hungersensations or appetite. The questionnaire 2905 presents a patient with aleading question, such as, “how hungry do you feel?” while the twoextremities 2906, 2907 of the scale line 2908 are anchored with wordsthat describe the feeling of least and maximum hunger. In one embodimentthe two extremities 2906, 2907 are described as “I am not hungry at all”and “I have never been more hungry”, respectively.

FIG. 29B illustrates a VAS questionnaire 2910 for assessing a feeling offullness. The questionnaire 2910 presents the patient with a leadingquestion, such as, “how full do you feel?” while the two extremities2911, 2912 of the scale line 2913 are anchored with words that describethe feeling of least and maximum fullness. In one embodiment the twoextremities 2911, 2912 are described as “Not at all full” and “Totallyfull”, respectively.

FIG. 29C illustrates a VAS questionnaire 2915 for assessing a feeling ofsatiation. The questionnaire 2915 presents the patient with a leadingquestion, such as, “how satisfied do you feel?” while the twoextremities 2916, 2917 of the scale line 2918 are anchored with wordsthat describe the feeling of least and maximum satiation. In oneembodiment the two extremities 2916, 2917 are described as “I amcompletely empty” and “I cannot eat another bite”, respectively.

FIG. 29D illustrates a VAS questionnaire 2920 for assessing a feeling ofsatiety. The questionnaire 2920 presents the patient with a leadingquestion, such as, “how much do you think you can eat?” while the twoextremities 2921, 2922 of the scale line 2923 are anchored with wordsthat describe the feeling of least and maximum satiety. In oneembodiment, the two extremities 2921, 2922 are described as “A lot” and“Nothing at all”, respectively.

Persons of ordinary skill in the art should appreciate that the leadingquestion and anchoring words at the two extremities of the scale, foreach questionnaire of FIGS. 29A through 29D, may be linguisticallymodified in alternate embodiments without departing from the assessmentobjective or the feeling to be assessed. For example, in an alternateembodiment the questionnaire 2920 the leading question is “How strong isyour desire to eat now?” while the two extremities 2921, 2922 aredescribed as “Extremely” and “Not at all”. Additionally, otherintermediate language may be used between the two extremes.

Also, VAS questionnaires can be designed to assess aspects such as, butnot limited to, health-related overall quality of life, degree ofnausea, degree of pain felt, degree of well-being, and degree ofdyspepsia. For example, in one embodiment, to assess nausea levels a VASquestionnaire may present a leading question, such as, “Do you feelnauseous?” while the two extremities of the scale are described as “Alot” and “Not at all”. In another embodiment, to assess health-relatedoverall quality of life or degree of well-being a VAS questionnaire maypresent a leading question, such as, “How satisfied are you with yourhealth as whole?” with the two extremities of the scale being describedas “completely dissatisfied” and “completely satisfied”. In yet anotherembodiment, to assess degree of dyspepsia a VAS questionnaire maypresent a leading question, such as, “Has your ability to eat or drink(including when, what, and how much) been disturbed by your stomachproblems in the last 2 weeks?” with the two extremities of the scalebeing described as “Extremely” and “Not at all”.

As discussed earlier, the Health Management application is capable ofcommunicating (via pairing or syncing) with a third party device(including a third party application software on an external device),with physiological sensors, configured to be worn on the human body,such as around the wrist, in order to monitor, acquire, record, and/ortransmit the physiological data, to receive and integrate exercise andweight loss information, along with one or more neuro-stimulationdevices of the present specification. It should be appreciated that thethird party device, whether it is a third party application software onan external device or a second external device entirely (such as, butnot limited to, a watch, a diabetes wearable pump, or another medicaldevice), is enabled to obtain information from the PEDP device of thepresent specification, either directly from the PEDP device, directlyfrom the Health Management application, or directly from a server indata communication with the PEDP device or the Heath Managementapplication of the present specification. Consequently, the third partyapplication or the second external device can display any informationgathered by the PEDP device and/or Health Management application,including patient diary inputs, the patient's level of hunger, thepatient's level of wellbeing, the patient's level of appetite, thestimulation settings, or an aggregate/composite weight managementperformance score which aggregates any of the data tracked by the thirdparty device with any of the data tracked by the PEDP device and/orHealth Management application to yield a single composite score.

The third party device, in various embodiments, may track one or anycombination of the following patient related data: heart rate, pulserate, beat-to-beat heart variability, EKG or ECG, respiration rate, skintemperature, core body temperature, heat flow off the body, galvanicskin response or GSR, EMG, EEG, EOG, blood pressure, body fat, hydrationlevel, activity level, oxygen consumption, glucose or blood sugar level,body position, pressure on muscles or bones, and/or UV radiationexposure and absorption or any other parameter listed in Tables 1 andTable 2 above, data representative of the air quality, soundlevel/quality, light quality or ambient temperature near the patient, orthe global positioning of the patient, patient's weight, food consumed,type and amount of activity or exercise (such as steps take, swimming,running).

Neuro-Stimulation Device Placement

In various embodiments, the neuro-stimulation device (such as theneuro-stimulation device 110 of FIG. 1A through 1C) of the presentspecification is placed and/or implanted at or near an ‘area ofinterest’ on the user's body to provide stimulation therapies for aplurality of conditions or treatments.

In various embodiments, the ‘area of interest’ comprises a dermatome. Asunderstood by persons of ordinary skill in the art, a dermatome is anarea of skin supplied by sensory neurons that arise from a spinal nerveganglion. There are 8 cervical nerves (C1 being an exception with nodermatome), 12 thoracic nerves, 5 lumbar nerves and 5 sacral nerves.Each of these nerves relays sensation from a particular region of skinto the brain.

In some embodiments, the ‘area of interest’ comprises a thoracicdermatome, such as the user's front, lateral and back T2 to T12dermatomes. In other embodiments, the ‘area of interest’ comprises adermatome, such as the user's front (anterior) and/or back (posterior)C5-T1 dermatomes in the hand and arm along with the front (anterior)C5-T1 dermatomes on the upper chest region (hereinafter togetherreferred to as ‘hand dermatomes’). In various embodiments, the ‘area ofinterest’ expressly excludes the back (posterior) C5-T1 dermatomes ofthe upper chest region since the back portions are inaccessible to theuser and therefore would need a medical practitioner to apply thedevices of the present specification.

In some embodiments, the ‘area of interest’ comprises at least one ofthe patient's T2 frontal, lateral and back thoracic dermatome, T3frontal, lateral and back thoracic dermatome, T4 frontal, lateral andback thoracic dermatome, T5 frontal, lateral and back thoracicdermatome, T6 frontal, lateral and back thoracic dermatome, T7 frontal,lateral and back thoracic dermatome, T8 frontal, lateral and backthoracic dermatome, T9 frontal, lateral and back thoracic dermatome, orT10 frontal, lateral and back thoracic dermatome.

In some embodiments, the ‘area of interest’ comprises at least one ofthe patient's C8 anterior or posterior dermatome located on thepatient's hand, wrist, elbow, and fingers, C8 anterior or posteriordermatome located on the patient's arm, C8 dermatome located on thepatient's upper trunk, T1 anterior or posterior dermatome located on thepatient's arm, T1 anterior or posterior dermatome located on thepatient's wrist, elbow, and hand, and T1 anterior or posterior dermatomelocated on the patient's upper trunk.

In some embodiments, the ‘area of interest’ comprises at least one ofthe patient's front, lateral and/or back C5, C6, C7, C8, T1, T2, T3, T4,T5, T6, T7, T8, T9, T10, T11, and T12 dermatomes.

In alternate yet less preferred embodiments, the ‘area of interest’comprises one or more meridians.

FIG. 17A is an illustration depicting the distribution 1700 of the frontand lateral, or frontal, T2-T12 dermatomes across a thorax and abdomen,that is trunk, of a human body while FIG. 17B is an illustrationdepicting the distribution 1730 of the posterior or back T2-T12dermatomes across the trunk. In various embodiments, theneuro-stimulation devices of the present specification are positionedjust underneath the surface of the epidermis on the front portion 1702,lateral portion 1704 and/or posterior or back portion 1735 of the T2-T12dermatomes, at a distance ranging from 0.1 to 30 mm below the skinsurface. The electrode(s) positioned within the pads or percutaneousskin patches of the neuro-stimulation device are then implantedunderneath the skin to provide electrical stimulation to the targeteddermatome(s).

The T2 to T12 dermatomes are anatomically identifiable as follows:

T2—At the apex of the axilla.

T3—Intersection of the midclavicular line and the third intercostalspace.

T4—Intersection of the midclavicular line and the fourth intercostalspace, located at the level of the nipples.

T5—Intersection of the midclavicular line and the fifth intercostalspace, horizontally located midway between the level of the nipples andthe level of the xiphoid process.

T6—Intersection of the midclavicular line and the horizontal level ofthe xiphoid process.

T7—Intersection of the midclavicular line and the horizontal level atone quarter the distance between the level of the xiphoid process andthe level of the umbilicus.

T8—Intersection of the midclavicular line and the horizontal level atone half the distance between the level of the xiphoid process and thelevel of the umbilicus.

T9—Intersection of the midclavicular line and the horizontal level atthree quarters of the distance between the level of the xiphoid processand the level of the umbilicus.

T10—Intersection of the midclavicular line, at the horizontal level ofthe umbilicus.

T11—Intersection of the midclavicular line, at the horizontal levelmidway between the level of the umbilicus and the inguinal ligament.

T12—Intersection of the midclavicular line and the midpoint of theinguinal ligament.

FIG. 17C is an illustration depicting the distribution 1701 of the frontand back, C5-T1 dermatomes across the hand 1705, arm 1710 and upperchest 1715 regions of a human body. In various embodiments, the PDEPneuro-stimulation devices of the present specification are positionedjust underneath the surface of the epidermis on the front portion 1720and/or back portion 1725 of the C5-T1 dermatomes on the hand 1705 andarm 1710 along with the front (anterior) C5-T1 dermatomes on the upperchest 1715, at a distance ranging from 0.1 to 30 mm below the skinsurface.

FIG. 17D is an illustration depicting the distribution of the C5-T1dermatomes across the hand 1705 and lower arm 1711 regions. In variousembodiments, the neuro-stimulation devices of the present specificationare positioned just underneath the surface of the epidermis on the front(palm) and/or back side of the hand 1705 targeting the C6-C8 dermatomesor on the front and/or back side of the lower arm 1711 (such as at awrist region, for example) targeting the C5 and T1 dermatomes, at adistance ranging from 0.1 to 30 mm below the skin surface.

Thus, the electrode(s) positioned on the pads or percutaneous skinpatches of the neuro-stimulation device are implanted underneath theskin to provide electrical stimulation to the targeted dermatome(s).

The C5-T1 dermatomes are anatomically identifiable as follows:

C5—On the lateral (radial) side of the antecubital fossa, justproximally to the elbow.

C6—On the dorsal surface of the proximal phalanx of the thumb.

C7—On the dorsal surface of the proximal phalanx of the middle finger.

C8—On the dorsal surface of the proximal phalanx of the little finger.

T1—On the medial (ulnar) side of the antecubital fossa, just proximallyto the medial epicondyle of the humerus.

FIG. 17E is a flow chart listing the steps involved in one method ofidentifying a proper placement location for a percutaneouselectro-dermal patch on a front thoracic surface of a patient, inaccordance with one embodiment of the present specification. At step1732, the physician or medical technician finds a midclavicular line ofthe patient. The person applying the device then progresses downwardfrom the midclavicular line to a bottom rib of a thoracic cage of thepatient at step 1734. From the bottom rib, at step 1736, the personapplying the device moves downward by 2 cm to identify a placement spot.At step 1738, the person applying the device places a top center portionof the percutaneous electro-dermal patch at the placement spot. Itshould be appreciated that the person applying the device may be theuser himself or a physician, depending upon the embodiment, as describedabove. In other words, the PEDP device of the present specification maybe self-implanted or self-administered by the user or implanted by aphysician or medical personnel so that one or more electrodes are placedor inserted percutaneously at an angle of insertion ranging from 10degrees to 90 degrees and up to a depth, ranging from 0.1 mm to 30 mm toenable stimulation depth through the user's skin ranging from 0.1 mm to30 mm.

Referring back to FIG. 1A, in various embodiments, at least one thoracicdermatome, from T2 to T12 and/or ‘arm dermatome’ or ‘hand dermatome’C5-T1, is stimulated by the neuro-stimulation device 110 to provideelectrical stimulation therapy by means of electrodes 118 placedpercutaneously within the skin.

In some embodiments, the neuro-stimulation device 110 stimulates areasin the T6 and/or T7 dermatome. In some embodiments, theneuro-stimulation device 110 stimulates areas in the C8 and/or T1dermatome on the hand of a patient. In still other embodiments, theneuro-stimulation device 110 stimulates areas in the T6, T7, C8 and/orT1 dermatomes.

In one embodiment, as shown in FIG. 18A, the neuro-stimulation device1800 stimulates the T6 dermatome, including meridians. In anotherembodiment, as shown in FIG. 18B, the neuro-stimulation device 1810stimulates the T7 dermatome. In yet another embodiment, as shown in FIG.18C, the neuro-stimulation device 1820 stimulates both the T6 and T7dermatomes. In some embodiments, referring to FIG. 18A, anneuro-stimulation device 1800 delivers, through one or more electrodespositioned within a pad or percutaneous skin patch, electricalstimulation 1802 above a rib (T6) and electrical stimulation 1804 belowthe rib (T6) to stimulate an intercostal nerve 1805 and the T6dermatome. In other embodiments, referring to FIG. 18B, anneuro-stimulation device 1810 delivers, through one or more electrodesdisposed in a pad or percutaneous skin patch, electrical stimulation1812 above a rib (T7) and electrical stimulation 1814 below the rib (T7)to stimulate an intercostal nerve 1815 and the T7 dermatome. In yetother embodiments, referring to FIG. 18C, an neuro-stimulation device1820 delivers, through one or more electrodes disposed in a pad orpercutaneous skin patch, electrical stimulation 1822 below a rib (T6)and above a rib (T7) and electrical stimulation 1824 below a rib (T7) tostimulate intercostal nerves 1825, 1835 and the T6 and T7 dermatomes.

In one embodiment, the neuro-stimulation device 1800 is positioned on avery specific portion of the patient's T6 dermatome. Specifically, thePEDP device 1800 is positioned on the left upper quadrant along themid-clavicular line, 2 cm below the ribcage at a 90 degree angle towardsthe abdominal wall at a depth of approximately 0.1 mm to 1 cm andpreferably at a depth of approximately 2 mm to 1 cm. In other words, thePEDP device 1800 is positioned at the intersection of two lines drawn ona standing patient: a first line vertically down from a mid-clavicle anda second line horizontally across from the xyphoid process. The firstand second lines would form an angle of 90 degrees on the right side andleft side of the anterior trunk of the patient.

In accordance with an aspect of the present specification, the T6dermatome is stimulated to treat conditions such as obesity,over-weight, eating disorders, metabolic syndrome and/or for appetitesuppression. In accordance with another aspect of the presentspecification, the T7 dermatome is stimulated to treat T2DM (Type 2Diabetes Mellitus). In accordance with yet another aspect of the presentspecification, up to two dermatomes, such as T6 and T7, aresimultaneously or alternatingly stimulated to treat multiple conditions(e.g., appetite suppression and T2DM). In accordance with another aspectof the present specification, the C8 or T1 dermatome is stimulated totreat conditions such as obesity, over-weight, eating disorders,metabolic syndrome and/or for appetite suppression. In accordance withyet another aspect of the present specification, up to two dermatomes,such as C8 and T1, are simultaneously or alternatingly stimulated. Instill further embodiments, T6, C8 and/or T1 dermatome is stimulated totreat conditions such as obesity, over-weight, eating disorders,metabolic syndrome and/or for appetite suppression, while the T7dermatome is stimulated to treat T2DM (Type 2 Diabetes Mellitus). Instill additional embodiments, multiple dermatomes are simultaneouslystimulated, for example any one or any combination of T6, T7, C8 and/orT1 dermatomes are stimulated simultaneously.

In some embodiments, the neuro-stimulation device 110 stimulates areasin the C8 and/or T1 dermatome on the hand of a patient. In oneembodiment, as shown in FIG. 19A, the neuro-stimulation device 1900,through one or more electrodes implanted in the user's skin, stimulatesthe C8 dermatome on the front (palm) or ventral side 1905 of the hand1910. In another embodiment, as shown in FIG. 19B, the neuro-stimulationdevice 1900, through one or more electrodes disposed in a pad orpercutaneous skin patch and implanted into the skin, stimulates the C8dermatome on the back or dorsal side 1906 of the hand 1910. In yetanother embodiment, as shown in FIG. 19C, the neuro-stimulation device1900, through one or more electrodes implanted in the user's skin,stimulates both the C8 and T1 dermatomes by being placed on the front orventral side of the lower arm or wrist region 1915.

It should be appreciated that, in various embodiments, theneuro-stimulation device 1900 is placed in-line with the patient'sfingers, such that a longitudinal axis 1901 of the neuro-stimulationdevice 1900 is approximately in the direction of the fingers. However,in various alternate embodiments the neuro-stimulation device may not beplaced in-line with the patient's fingers. In various embodiments, theneuro-stimulation device 1900 is placed on a non-dominant hand of thepatient. In some embodiments, the neuro-stimulation device 1900 ispreferably placed on the back or dorsal side of the hand (as shown inFIG. 19B) as the patient's palm (ventral side) comes into contact withmany surfaces in daily routine that may cause damage to theneuro-stimulation device 1900.

In accordance with an aspect, the neuro-stimulation device 1900 issufficiently flexible so that it conforms to the contour of the user'shand 1910 and does not interfere in free movement of the hand 1910.Referring back to FIG. 1A, to enable sufficient flexibility of theneuro-stimulation device 110 (that is, neuro-stimulation device 1800configured as a percutaneous skin patch as shown in FIGS. 19A through19C) the underlying electronics such as the microcontroller 112,transceiver 114, the pulse generator 116 and the power management module120 including the receptor slots 130 are mounted on flexible plasticsubstrates, such as polyimide, PEEK (Polyether Ether Ketone) ortransparent conductive polyester film—to form flex circuits.Alternatively, the underlying electronics are substantially miniature sothat their rigid substrate, in some embodiments, do not need to flexover their small area. In some embodiments, the power management module120 including the receptor slots 130, the actuators 122 and theindicators 124, 126 are physically separated or at a distance from theelectronic circuitry such as the microcontroller 112, transceiver 114,and the pulse generator 116 to enable increased flexibility. In variousembodiments, the housing 111 of the neuro-stimulation device 110 is of aflexible material such as silicone, rubber or any other flexible polymerknown to persons of ordinary skill in the art.

In some embodiments, the neuro-stimulation device, through one or moreelectrodes implanted in the user's skin, is configured to stimulate theC8 dermatome on the front (palm side) or ventral side as well as theback or dorsal side of the user's hand. In one embodiment, as shown inFIG. 20A, the neuro-stimulation device 2000 comprises a first patchportion 2015, a second patch portion 2020 and a third patch portion orbridge 2025 connecting the first and second patch portions 2015, 2020.In some embodiments, the first and second patch portions 2015, 2020 aresubstantially semi-circular shaped that are connected by a substantiallyrectangular bridge 2025 such that the neuro-stimulation device 2000forms an approximate ‘hourglass’ shape. In another embodiment, as shownin FIG. 20B, the first and second patch portions 2015′, 2020′ aresubstantially rectangular that are connected by a substantiallyrectangular bridge 2025′ such that the neuro-stimulation device 2000′forms an approximate ‘H’ shape. In various embodiments, the bridge 2025,2025′ is narrow (that is, the width is substantially less than thelength of the bridge) to increase flexibility of this segment of theneuro-stimulation device 2000, 2000′. It should be appreciated that the‘hourglass’ and ‘H’ shaped configurations of FIGS. 20A, 20B arenon-limiting examples of the various shapes that the neuro-stimulationdevice may have in various embodiments.

In some embodiments, all three patch portions 2015, 2020 and 2025 areadhesive. However, in alternate embodiments only the first and secondpatch portions 2015, 2020 are adhesive while the bridge portion 2025 isnon-adhesive to improve comfort, wearability tolerance and overallflexibility of the patches 2000, 2000′. The non-adhesive bridge portion2025 may be configured into a thinner portion relative to the adhesivefirst and second adhesive patch portions 2015, 2020.

During use, the neuro-stimulation devices 2000, 2000′ respectively wraparound the edge 2011 of the hand 2010 such that the first patch portion2015 adheres to or lies on the front (palm) or ventral side 2005, thesecond patch portion 2020 adheres to or lies on the back or dorsal side2006 while the bridge 2025 wraps around the edge 2011 of the hand 2010.In accordance with an aspect of the present specification, a firstelectrode is disposed in the first patch portion 2015 to stimulate theC8 dermatome on the ventral side 2005 and a second electrode is disposedin the second patch portion 2020 to stimulate the C8 dermatome on thedorsal side 2006 of the hand 2010.

In some embodiments, the neuro-stimulation devices 2000, 2000′ areconfigured such that the underlying electronic circuitry including thepower management module are disposed on one of the first or second patchportions 2015, 2020. Thus, referring to FIGS. 1A, 20A, 20B theneuro-stimulation device 110 is configured or disposed as patches 2000,2000′ of FIGS. 20A, 20B such that the microcontroller 112, transceiver114, pulse generator 116, the power management module 120 including thereceptor slots 130, actuators 122 and the indicators 124, 126 arelocated on either the first or the second patch portions 2015, 2020. Inone embodiment, the microcontroller 112, transceiver 114, pulsegenerator 116, the power management module 120 including the receptorslots 130, actuators 122 and the indicators 124, 126 are located on thesecond patch portion 2020 i.e., the patch portion that adheres to theback or dorsal side 2006 of the hand 2010 to avoid damage to theelectronic components from daily use.

In other embodiments, the neuro-stimulation devices 2000, 2000′ areconfigured such that the underlying circuitry and the power managementmodule are distributed between the first and second patch portions 2015,2020. Thus, referring to FIGS. 1A, 20A, 20B the neuro-stimulation device110 is configured or disposed as patches 2000, 2000′ of FIGS. 20A, 20Bsuch that the microcontroller 112, transceiver 114, pulse generator 116the power management module 120 including the receptor slots 130,actuators 122 and the indicators 124, 126 are distributed and thereforephysically separated between the first and second patch portions 2015,2020 to improve flexibility of the neuro-stimulation devices 2000,2000′. In one embodiment, the microcontroller 112, transceiver 114,pulse generator 116, actuators 122 and the indicators 124, 126 arelocated on, say, the first patch portion 2015 (that adheres to theventral or palm side 2005 of the hand 2010) whereas the power managementmodule 120 including the receptor slots 130 is located on the secondpatch portion 2020 (that adheres to the dorsal or back side 2006 of thehand 2010). In another embodiment, the microcontroller 112, transceiver114, pulse generator 116, actuators 122 and the indicators 124, 126 arelocated on, say, the second patch portion 2020 (that adheres to thedorsal or back side 2006 of the hand 2010) whereas the power managementmodule 120 including the receptor slots 130 is located on the firstpatch portion 2015 (that adheres to the ventral or palm side 2005 of thehand 2010).

Still referring to FIGS. 1A, 20A, 20B, in one embodiment, the first andsecond electrodes 118 as well as the sensors 135 are disposed on thefirst patch portion 2015 i.e., the patch portion that adheres to thefront (palm) or ventral side 2005 of the hand 2010. In anotherembodiment, the first and second electrodes 118 are disposed on thefirst patch portion 2015 while the sensors 135 are located on the secondpatch portion 2020. In yet another embodiment, the first and secondelectrodes 118 are disposed on the second patch portion 2020 while thesensors 135 are located on the first patch portion 2020. In stillfurther embodiments, the first and second electrodes 118 arerespectively disposed on the first and second patch portions 2015, 2020while the sensors 135 are located on either the first or the secondpatch portion 2015, 2020.

It should be noted that while in various embodiments, theneuro-stimulation devices of FIGS. 19A, 19B, 19C, 20A and 20B have beenillustrated as being placed at locations on the hand of the user, invarious alternate embodiments these neuro-stimulation devices may beplaced at other points to stimulate the C5-C8 and/or T1 dermatomes onthe user's arms or upper chest regions as well.

Thus, in accordance with some aspects of the present specification,electrical stimulation to a depth ranging from 0.1 mm to 30 mm of thepatient's dermis (using the neuro-stimulation device 110 of FIG. 1A)provides for treatment of appetite suppression, ghrelin productionmodulation, eating disorders, excessive weight or over-weight, obesity,metabolic syndrome and diabetes. In various embodiments, a stimulationdepth through the patient's skin ranges from 0.1 mm to 0.2, 0.3, 0.4,0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60 mm or any increment therein.

Mechanisms of Action

The therapeutic objectives of the presently disclosed embodiments may beeffectuated by one or more of the following mechanisms of action. In afirst mechanism of action, the pain of hunger is negated, operatingunder one or more predefined stimulation parameters. Small diameternerve fibers carry pain stimuli through a theoretical “gate mechanism”but larger diameter nerve fibers can inhibit the transmission of painstimuli by the smaller nerves, in effect blocking or closing thistheoretical gate. It is believed that by stimulating the large nervefibers, the gate can be closed to block the pain and thereby block anysensation of hunger. In a second mechanism of action, the production ofendorphins, which are natural pain relieving hormones produced by thebody, may be upregulated or increased, operating under one or morepredefined stimulation parameters, again thereby blocking any sensationof hunger.

In a third mechanism of action, the present embodiments, operating underone or more stimulation parameters, causes a somato-somatic,somato-autonomic and/or a somato-visceral reflex with resulting afferentcentral as well as efferent visceral effects. In various embodiments,electrical stimulation through the dermis of the dermatomes disclosedherein creates a somato-autonomic reflex with sensory nerves thatconnect specifically to the stomach as an efferent pathway. As aconsequence of this parasympathetic stimulation, the stomach slows downits emptying process and increases the feeling of fullness or satiation,which translates into a reduction in appetite. Similarly, in variousembodiments, electrical stimulation through the dermis of certaindermatomes, such as the T7 dermatome, also creates a somato-autonomicreflex with sensory nerve endings to dermatome T7 as an afferent pathwayand parasympathetic branches of the sensory nerves which stimulate thepancreatic gland as an efferent pathway.

In a fourth mechanism of action, the present application discloses amethod of modifying an individual's perception of food, or otherwiseundermining their association of positive feelings with food, andthereby increasing his or her aversion to food intake comprising:providing a percutaneous electrical dermal patch adapted to adhere tothe patient's epidermal layer, wherein said electrical dermal patchcomprises a controller, at least one electrode adapted to be implantedinto said patient's skin, and a pulse generator in electricalcommunication with the controller and said at least one electrode,defining a plurality of stimulation parameters, and programming thepulse generator to generate a plurality of electrical pulses using saidplurality of stimulation parameters, wherein said plurality ofstimulation parameters are defined such that, after applying at leastone stimulation to the patient's nerves, the patient has an increasedaversion to food intake. In this regard, the stimulation parameters maybe defined such that a) the stimulation is painful, b) the stimulationis coordinated with, and automatically triggered during, the person'sactual food intake times, such times being programmed into thecontroller or pulse generator either directly or from an external deviceand automatically triggering a stimulation at the appropriate times, c)the stimulation is coordinated with, and automatically triggered during,times of day other than the person's actual food intake times, suchtimes being programmed into the controller or pulse generator eitherdirectly or from an external device and automatically triggering astimulation at such times, and d) the stimulation is manually triggeredat any given time by the patient, either directly via an interface onthe PEDP or via the external device, as the patient may require. Thebenefit of this method is that it achieves, in addition to thephysiological effects of appetite modulation, the psychological effectof associating a negative sensation (electrical stimulation) with foodintake, thereby undermining the otherwise positive associations theindividual has with food and, therefore, one of the key psychologicalimpetuses for compulsive eating. In this regard, the present inventionachieves an aversion to food intake, in addition to a decrease inappetite.

In a fifth mechanism of action, the presently disclosed embodimentsselectively cause electrical central nervous stimulation over electricalspinal stimulation. Electrical stimulation in the perceptive range iscentral (sensory) and in the non-perceptive range is spinal (autonomic).Electrical stimulation above a sensation reaction threshold results inselective central stimulation while electrical stimulation below thesensation reaction threshold results in selective spinal stimulation.Therefore, determining the sensation reaction threshold in a patientallows for the adjustment of electrical stimulation parameters forselective central or spinal stimulation to modulate the patient'sappetite level.

FIG. 21A is a flow chart illustrating the steps involved in oneembodiment of a method of determining stimulation reaction thresholdsand using a percutaneous electro-dermal patch (PEDP) device to suppressappetite in a patient. At step 2122, the PEDP device is positioned onthe patient's body, such that the at least one electrode can beimplanted just underneath the patient's skin. In various embodiments,the PEDP device is either self-implanted by the patient himself or isimplanted by a physician or medical personnel. At step 2124, a centralelectrical stimulation reaction threshold for the patient is determined.Then, at step 2126, a spinal electrical stimulation reaction thresholdfor the patient is determined. A microcontroller of the PEDP device isthen programmed, at step 2128, such that at least one of a pulse width,pulse amplitude, and pulse frequency of delivered electrical stimulationis set above the spinal electrical stimulation reaction threshold butbelow the central electrical stimulation reaction threshold. At step2130, the PEDP device then generates a plurality of electrical pulsesdefined by the pulse width, pulse amplitude, and pulse frequency set atstep 2128.

FIG. 21B is a flow chart illustrating the steps involved in anotherembodiment of a method of determining stimulation reaction thresholdsand using a percutaneous electro-dermal patch (PEDP) device to suppressappetite in a patient. At step 2142, the PEDP device is positioned onthe patient's body, such that the at least one electrode can beimplanted just underneath the patient's skin. In various embodiments,the PEDP device is either self-implanted by the patient himself or isimplanted by a physician or medical personnel. At step 2144, a maximumtolerable electrical stimulation reaction threshold, which can bemeasured as a pain sensation, for the patient is determined. Then, atstep 2146, a spinal electrical stimulation reaction threshold for thepatient is determined. A microcontroller of the PEDP device is thenprogrammed, at step 2148, such that at least one of a pulse width, pulseamplitude, and pulse frequency of delivered electrical stimulation isset above the spinal electrical stimulation reaction threshold but belowthe maximum tolerable electrical stimulation reaction threshold. At step2150, the PEDP then generates a plurality of electrical pulses definedby the pulse width, pulse amplitude, and pulse frequency set at step2148.

In a sixth mechanism of action, the percutaneous electro-dermal patch(PEDP) devices of the present specification stimulate specificdermatomes as described above to modulate ghrelin and suppress appetite.The gastric mucosa plays a role in ghrelin-induced gastric contractions.Intrinsic primary afferent neurons (IPAN), which comprise multi-axonalinterneurons, may be involved in passing signals from the mucosa to themyenteric plexus. Ghrelin may stimulate and modulate gastriccontractions through cholinergic, adrenergic, serotonergic, and/oropioidergic actions and/or via nitric oxide synthase in the myentericplexus. The stimulatory effects of ghrelin on gastric motility aremediated by the direct stimulation of the intrinsic enteric neuralpathway and capsaicin-sensitive afferent neurons. There exists a closeinteraction between ghrelin and enteric neurotransmission, involving thestimulation of the excitatory neural system and/or the suppression ofthe inhibitory neural system via ghrelin receptors, under stimulation ofthe intrinsic neural pathways. Ghrelin secretion during fasting isinduced by adrenergic agents (locally released norepinephrine), releasedby sympathetic neurons acting directly on B1 receptors on ghrelinsecreting cells of the stomach, resulting in fasting-induced elevationin plasma ghrelin levels.

Sympathetic stimulation at certain dermatomes, such as dermatome T6,causes a somato-visceral arc reflex which causes inhibition of the B1adrenergic (sympathetic) neurons that produce ghrelin. This results in adecrease in ghrelin levels. This decrease in ghrelin causes activity inthe enteric nervous system and intrinsic primary afferent neuronscontained in the gastric mucosa (necessary as a final step in ghrelin'saction on gastric and antral motility).

Therefore, in various embodiments of the present specification, the PEDPdevices are believed to suppress appetite via the following mechanism.To begin, a PEDP device delivers electrical stimulation to the cutaneousnerves at dermatome T6 (or any of the other dermatomes described in thepresent specification), activating the somato-visceral reflex describedabove. In some embodiments, the PEDP device delivers electricalstimulation to the cutaneous nerves at dermatomes T5-T10. Stimulation ofthe B1 adrenergic plexus (neurons), which is inhibitory in nature,results in decreased production of fasting ghrelin. This leads todecreased activity in the enteric nervous system and in intrinsicprimary afferent neurons (responsible for the final steps necessary forghrelin action on gastrointestinal motility). The decreased plasmaghrelin levels result in appetite suppression as well as decreasedgastric motility and decreased gastric emptying time.

In a sixth mechanism of action, the percutaneous electro-dermal patch(PEDP) devices of the present specification use electrical stimulationto effect a reduction in antral activity resulting in reduction ingastric motility and slowing of gastric emptying. Somatic stimulation ofthe T2-T12 and/or C5-T1 dermatomes, using the neuro-stimulation deviceof the present specification, affects modulation of the gastrointestinalphasic pressure activity resulting in reduction in antral motility andan increase in plasma beta-endorphin levels. Thus, somatic stimulationcauses reduced post-prandial antral phasic pressure activity, slowing ofgastric emptying and therefore a feeling of satiety over increasedperiods of time between meals. FIG. 33A is a chart 3300 illustratingmean cumulative changes (in 20 minutes increments) of antral motilityindices during sham stimulation sessions 3305, stimulation sessions 3310targeted to hand dermatomes C8 and/or T1 and stimulation sessions 3315targeted to thoracic dermatomes T2-T12. Note the effect on antralmotility of the hand and abdomen stimulation sessions. FIG. 33B is achart 3301 illustrating maximum plasma endorphin levels in pg/ml relatedto sham stimulation sessions 3306, stimulation sessions 3311 targeted tohand dermatomes C5-C8 and/or T1 and stimulation sessions 3316 targetedto thoracic dermatomes T2-T12. Note the increase in endorphin levels asa result of the hand and abdomen stimulation sessions. In additionalmechanisms of action, the percutaneous electro-dermal patch (PEDP)devices of the present specification use electrical stimulation tomodulate gut microbiota to improve the ratio of favorable to unfavorablegut bacteria, modulate secretions of a plurality of hormones such asserotonin, glucagon-like peptide 1 (GLP1), and leptin, reduce serumlevels of lipopolysaccharide (LPS), improve metabolic inflammation andinsulin resistance, modulate resting metabolic rate (RMR) and byimproving glucose homeostasis. The specific therapeutic objectivesrelated to each of the above listed hormones and other physiologicalmarkers are further discussed below.

Stimulation Patterns/Protocols to Drive Therapy

As discussed earlier, the user's plurality of health relatedinformation, such as the user's hunger profile, standard eating andmeals profile, actual eating and meals profile, energy balance, weighttrends, glucose data, stimulation induced nausea, dyspepsia andhabituation events—is utilized by the Health Management application tosuggest and/or implement a plurality of recommendations comprisingstimulation patterns or protocols, medication (such as an amount ofinsulin intake, for example), dietary and/or activities plans. It shouldbe appreciated that this integrated system provides users with a degreeof independence and encourages patient compliance. Notwithstanding theabove, however, the present application does apply to having physiciansset or modify the stimulation protocols, either directly programming thePEDP, programming the PEDP through the companion device, or remotelycommunicating a desired protocol from a remote server or third partycomputing device to either the PEDP directly or via the companiondevice.

In various embodiments, recommendations related to stimulation patternsor protocols comprise driving, setting, customizing or adjusting aplurality of stimulation parameters such as, but not limited to, thenumber of stimulation sessions per day; duration of each stimulation;time or moment of application of the stimulation sessions; intensity ofstimulations, stimulation pulse shape, frequency, width and amplitude;stimulation duty cycle; stimulation continuity profile; minimum andmaximum overall duration or course of stimulation treatment in days,weeks or months. Following are exemplary standard setting ranges forsome of the stimulation parameters:

-   -   Pulse Width: 10 μsec to 10 msec    -   Pulse Amplitude: 100 μA to 500 mA, less than 60 mA, 100 μA to        500 mA, 1 mA to 30 mA, 15 mA to 30 mA, 5 mA to 45 mA, and any        increment therein    -   Pulse Frequency: 1 Hz to 10,000 Hz, preferably 1 Hz to 100 Hz    -   Pulse Shape: Monophasic, biphasic, sinusoidal    -   Duty Cycle: 1% to 100%    -   Stimulation Session Duration: 1 min to 120 min or 50 ms to 120        min or substantially continuously    -   Number of Stimulation Sessions/Day: 1 to 24    -   Number of Sessions/Week: 1 to 168 or 1 to substantially        continuously    -   Daily Pre-Prandial Stimulations: half hour to an hour prior to        each meal every day, as most patients typically report hunger        peaking just prior to meals    -   Burst Mode (that is, a burst of programmable pulses at a rate):        0.1 Hz to 100 Hz    -   Ramp Up/Down Mode (that is, the time it takes to go from no        stimulation to a peak or steady state (Ramp Up) and the time it        takes to go from peak or steady state stimulation to no        stimulation (Ramp Down)): 0.1 sec to 60 sec    -   Modulated Mode: Range between 1%-100% amplitude, modulating        up/down over a period of 0.1 sec-60 sec; modulation can be        linear or sinusoidal; that is, in “modulated mode” the amplitude        varies between 1% and 100% of a target amplitude (such as 10 mA)        and this amplitude variation occurs over a period of 0.1 seconds        to 60 seconds    -   Electrode impedance (that is, the electrode-tissue interface        impedance): 100 ohms to 5 kilo-ohms, 10 ohms to 5 kilo-ohms, 200        ohms to 1000 ohms, or 1 kilo-ohms to 100 kilo-ohms

In some embodiments, the neuro-stimulation device provides electricalstimulation having the following parameters which are adjustable by thepatient using the companion device:

-   -   Monophasic pulse shape with an active charge balancing phase    -   Pulse Width: 25 μsec to 400 μsec in steps of 25 μsec    -   Pulse Amplitude: 1 mA to 50 mA in steps of 1 mA    -   Pulse Frequency: from 1 Hz, 5 Hz, 10 Hz, 15 Hz, 20 Hz, 25 Hz, 30        Hz, 40 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 150 Hz,        200 Hz    -   Stimulation Session Duration: from 5 min to 60 min in steps of 5        min

In some embodiments, the neuro-stimulation device provides electricalstimulation having the following parameters which are adjustable by thepatient using the companion device:

-   -   Pulse Width: 100 μsec to 500 msec, preferably 10 μsec to 100        msec    -   Pulse Amplitude: 1 μA to 1 mA    -   Pulse Frequency: 0.1 Hz to 1 kHz    -   Stimulation Session Duration: 1 min to 24 hr    -   Number of Stimulation Sessions/Day: 1 to 24    -   Number of Sessions/Week: 1 to substantially continuously

It should be appreciated that any initial or default stimulationparameters, which are implemented upon starting the device and withoutthe benefit of any user input regarding their appetite, hunger, satietylevel, satiation level, fullness level, well-being status, nausea statusor other information, may be universally fixed for all persons or may bebased upon any one or a combination of the following parameters of theperson: age, gender, ethnicity, weight, body mass index, body fatpercentage, and/or race. Therefore, stimulation dosing may be initiallybased on categorizing the individual into one or more template groupsand choosing a corresponding protocol. For example, one may classifyindividuals into various groups (a BMI greater than 40, a BMI of 35 to39, a BMI of 30 to 34, and a BMI of 25 to 29) and apply a standardstimulation scheme for all individuals within that classification. Thesame could apply to a combination of age and gender for example (females65 and over, females 55 to 64, females 45 to 54, females 35 to 44,females 25 to 34, females 24 and under, males 65 and over, males 55 to64, males 45 to 54, males 35 to 44, males 25 to 34, males 24 and under).Additionally, the initial stimulation settings may be based on anyparameters indicative of the patient's extent of appetite, or hunger,satiety level, satiation level, or fullness level.

It should further be appreciated that any selected stimulationparameters may be titrated for a given patient. Specifically, they maybe adjusted upward or downward based on the amount of stimulation feltby the patient and/or immediately reported feelings of pain, nausea, orother discomfort.

In some embodiments, the stimulation continuity profile may be, for eachstimulation session duration the stimulation profile applied,continuous; intermittent including short intervals of Y seconds of nostimulation; step-up stimulation wherein the stimulation amplitudeand/or frequency increases at a predefined rate from commencement tocompletion of a stimulation session duration; or step-down stimulationwherein the stimulation amplitude and/or frequency decreases at apredefined rate from commencement to completion of a stimulation sessionduration. In some embodiments, the stimulation continuity profile mayvary on a day to day basis. For example, for a treatment duration of,say, 4 weeks the stimulation profile applied may be at least one ofcontinuous wherein the number and/or intensity of stimulation does notvary throughout the treatment; step-up stimulation wherein the intensityand number of sessions per day increase at a predefined rate on a dailyor weekly basis; step-down stimulation wherein the intensity and numberof sessions per day decrease at a predefined rate on a daily or weeklybasis.

In some embodiments, the time or moment of application of stimulationsessions may be, for example, ‘t’ minutes before meals such asbreakfast, lunch, snack, dinner, wherein T is within a range of 1 min to150 min; right before going to bed; at the onset of hunger and/or rightbefore an expected hunger event based on the user's recorded hungerprofile.

In accordance with an aspect of the present specification, the user aswell as the remote patient care facility or personnel are able tocontrol and adjust the plurality of stimulation parameters through theHealth Management application and/or by the user via actuators 122 suchas buttons or switches of FIG. 1A. In some embodiments, the remotepatient care facility or personnel is authorized to control and adjustall stimulation parameters while the user is enabled to control andadjust a subset of the stimulation parameters with or withoutauthorization/approval of the remote patient care facility or personnel.For example, the user may be allowed to change the number of stimulationsessions per day from, for example, 2 sessions per day to 1 session perday; stimulation session duration from, for example, 30 minutes to 15minutes; and/or stimulation pulse amplitude from, for example, 20 mA to150 μA. In one embodiment, the maximum change is limited to a predefinedamount or multiple of the prior settings.

In a preferred embodiment, the user is able to increase the stimulationpulse amplitude from a minimal default amplitude setting of, say, 100 μAto a ‘sensory threshold’ corresponding to amplitude where the user canjust feel the stimulation. The user may then save the ‘sensorythreshold’ setting and continue stimulation at this setting. The sensoryperception varies from person to person and therefore in variousembodiments the ‘sensory threshold’ ranges from about 5 mA to 10 mA onthe lower side and from about 20 mA to 30 mA on the higher side.

In some embodiments, a stimulation protocol includes alternatingstimulation sessions between a first session having a low pulsefrequency, for example, less than 50 Hz, followed by a second sessionhaving a high pulse frequency, for example, greater than 50 Hz.

In still further embodiments, the user may be able to control and adjustthe subset of stimulation parameters within the standard settingsranges, such as those described above, or within a narrower band ofrange or constrained range within the standard settings ranges. Forexample, the user may be allowed to modify the stimulation pulse width,amplitude and frequency by no more than +/−50% from the original,default or standard setting. In another example, the user may be allowedto modify all stimulation parameters by +/−10% (from the original,default or standard setting) except for allowing the amplitude todecrease unbounded in order to address safety and/or comfort reasonsUser modification of the stimulation parameters beyond the constrainedrange may require authorization from the remote patient care facility orpersonnel. In some embodiments, the range within which the user is ableto control and adjust the subset of stimulation parameters is set by theremote patient care facility or personnel. Also, in some embodiments,the user may be allowed to control and adjust stimulation parameterswithin a first range at the onset of therapy, but as therapy progresses(for example, after 2 to 3 weeks) the user is allowed to control andadjust stimulation parameters within a second range wherein the secondrange is narrower, limited or constrained compared to the first range.

It should be appreciated that the type and number of stimulationparameters that the user is allowed to control and adjust can vary inmultiple embodiments.

In accordance with an aspect of the present specification, the HealthManagement software application provides a plurality of pre-configureddefault or standard stimulation protocols to drive therapy for aplurality of conditions such as obesity, over-weight, eating disorders,metabolic syndrome or appetite suppression and T2DM, as examples.

Example Stimulation Protocols for Treating Conditions of Obesity,Over-Weight, Eating Disorders, Metabolic Syndrome or AppetiteSuppression and/or T2DM

In various embodiments, a standard stimulation protocol, for stimulatingthe T6, C8 and/or T1 dermatome for treating conditions of obesity,over-weight, eating disorders, metabolic syndrome or for appetitesuppression and the T7 dermatome for treating T2DM, may comprise aplurality of pre-configured standard settings such as at least threesetting options, for example mild, optimal, intense. For example, anembodiment of a standard optimal stimulation protocol comprises two 30minute sessions a day, 30 to 45 minutes before lunch and right beforebed or after a specific time, say, after 8 or 9 pm, at an intensity thatdoesn't bother patient, but can still be felt by them, such as at afrequency of 20 Hz and at a ‘sensory threshold’ amplitude of 10 mA. Astandard mild stimulation protocol comprises one 20 minute session aday, 30 to 45 minutes before lunch or right before bed or after aspecific time, say, after 8 or 9 pm, at a frequency of 20 Hz and at a‘sensory threshold’ amplitude of 5 to 35 mA. A standard intensestimulation protocol comprises three 30 minute sessions a day, 30 to 45minutes before lunch, right before bed and also after a specific time,say, after 8 or 9 pm, at a frequency of 40 Hz and at a ‘sensorythreshold’ amplitude of 10 mA. In some embodiments, a latency effect isencountered with stimulation wherein the stimulation is provided for aspecific amount of time and the effect is not witnessed until a certainamount of time has passed and/or the effect remains for a certain amountof time post stimulation. For example, in one embodiment, ghrelinremains suppressed for at least several weeks post stimulation.

Some embodiments additionally comprise a custom setting option thatallows the user to adjust or set the subset of stimulation parameters,which he is allowed to control, within constrained ranges. It should beappreciated that the number of pre-configured settings (such as mild,optimal, intense) may vary across various embodiments. Also, thestimulation protocol, with its mild, optimal and intense configurations,is only exemplary and may vary across various embodiments and fortargeting specific conditions such as only appetite suppression or T2DM.For example, a stimulation protocol directed towards ghrelin modulation,and therefore appetite modulation, may include a stimulation pulse widthof 200 μsec, pulse amplitude corresponding to the user's ‘sensorythreshold’ such as 20 mA, pulse frequency of 20 Hz, stimulation sessionduration of 30 minutes and one session per day for 4 weeks. Anotherexample stimulation protocol directed towards appetite suppression mayinclude a 15 minutes stimulation session, using a current frequency of 6Hz of 0.1 milliseconds (ms) duration starting at intensities of 1 to 20milliampere (mA) until the intensity reaches the user's ‘sensorythreshold’.

In accordance with an aspect of the present specification, the HealthManagement application recommends and periodically adjusts thestimulation protocols or patterns based on the user's health relatedinformation, such as the user's hunger profile, standard eating andmeals profile, actual eating and meals profile, energy balance, weighttrends, glucose data and stimulation induced nausea, dyspepsia,habituation events. For example, if the user's energy balance ispositive by about 5% beyond a pre-defined positive energy balancethreshold at a certain calories consumption schedule per day, asdictated by the user's standard regular eating and meals profile, andthe user is also found to be over-weight or obese, the Health Managementapplication may suggest commencing with the optimal stimulation protocolfor two weeks along with an activities regiment comprising, for example,daily or weekly goals of walking, exercising, running, swimming directedtowards increasing the user's calories expenditure. The HealthManagement application monitors compliance of the user to therecommended optimal stimulation protocol and the activities regimenthroughout the two weeks. The user's resulting energy balance andcompliance profile is recorded and displayed to the user in the form ofcharts, graphs, tables or any other visual format as would beadvantageously evident to persons of ordinary skill in the art. At thecommencement or throughout the duration of the therapy, the HealthManagement application may also recommend a standard or customizeddietary plan to the user as part of a holistic approach to improvingeffectiveness of the stimulation therapy. For example, Table 3 shows a1200 Kcal/day customized diet plan (from a plurality of such diet planspre-stored within the Health Management application) recommended by theHealth Management application:

TABLE 3 Mean values of carbohydrates 51%; proteins 23%; fats 26% MealContents Breakfast Skimmed milk 200 cc or 2 natural skimmed yoghourtsBread 50 g or 2 toasts of “biscotti” type bread Mid- Fruit (one piece,100 g of apple, pear, orange, melon or morning kiwi) Meal and Maincourse to choose from: dinner Vegetables 200 g: spinach, chard,eggplant, watercress, endive, lettuce, cauliflower, mushroom, leek,asparagus, escarole, cabbage, cucumber, peppers, tomatoes, alternatingcooked or in a salad, or 150 g of green beans, beet, carrot, artichokeor Brussels sprouts Vegetable soup Skimmed broth (free consumption)Andalusian gazpacho, provided it is prepare without bread and a smallamount of oil, remembering not to exceed the ration of oil for the wholeday Pasta, semolina, rice or tapioca soup (15 g dry) Second course tochoose from: White fish 120 g Chicken, turkey, rabbit, veal meat 100 gEggs, one unit Tomatoes and lettuce salad (or any other raw vegetable)150 g only once a day Dessert, to choose from: Fruit (one piece, 100 gof apple, pear, orange, kiwi, melon or 200 g of watermelon) Bread 25 gAfternoon 200 cc of skimmed milk, just milk or with coffee or tea snackOil for all 30 cc (2 soup spoons) day

If the user's energy balance and/or weight trend shows improvement, forexample the energy balance reduces up to or below the positive energybalance threshold and/or the rate of weight reduction is withinpre-defined acceptable limits, the Health Management application mayrecommend the user to shift to the mild stimulation protocol for thenext two weeks. On the other hand, if the user's energy balance and/orweight trend deteriorates or remains same as at the commencement of thestimulation therapy due the user's non-compliance to the activitiesregimen (as a result of which the user is not burning a requisite amountof calories), for example if the user's energy balance is found to bepositive by about M %, wherein M %>L % and/or the rate of weightreduction is below the pre-defined acceptable limits or there is nosignificant weight reduction, the Health Management application mayrecommend the user to shift to the intense stimulation protocol for thenext two weeks.

Various embodiments also comprise allowing on-demand stimulation inaddition to or in lieu of the standard stimulation protocolpre-configured settings (for example mild, optimal, intense). On-demandstimulations, also referred to hereinafter as “rescues”, are applied atthe onset of unplanned hunger events and/or at a potential occurrencesof hunger events as known from the user's hunger profile. While the useris allowed on-demand stimulations as well as customized stimulationprotocols, in various embodiments the Health Management application isprogrammed to ensure (such as by continuous monitoring, limited orrestricted control access to only the subset of stimulation parametersand/or restricting the user control access to only a constrained rangewithin the standard settings ranges) that the user does not over orunder stimulate, thereby resulting in habituation or ineffectivestimulation. For example, the user may be allowed to add to the numberof daily sessions, over and above those scheduled based on the standardprotocol settings (mild, optimal, intense), but subject to somelimitations or restrictions. For example, the user may have fiveadditional “rescues” in the first month of the stimulation therapy,declining to 4 daily in the second month, and 3 daily in the third monthof therapy. It should be appreciated that the limitations are criticalto avoiding habituation over time. Also, the number of stimulationsessions may be restricted and then may decline and/or the stimulationintensity, such as the amplitude and frequency, may be allowed to beadjusted up or down by a set amount, for example by +/−10%.

In some embodiments, the Health Management application is configured tobe in communication with an insulin pump that the user may be using toinfuse insulin while the neuro-stimulation device of the presentspecification uses a continuous glucose sensor, as one of the sensors135 of FIG. 1A, to monitor the user's glucose level. Thus, for exampleif the user's glucose level is higher than the normal, by a predefinedglucose threshold, the Health Management application may recommendcommencing with the optimal stimulation protocol along with a diet plan,such as that illustrated in Table 3, for a period of 2 weeks. In variousembodiments, a predefined glucose threshold comprises a fasting bloodsugar level greater than 80 mg %. The Health Management applicationcontinuously monitors the user's glucose levels during the therapy andallows the user to suppress post-prandial glucose levels. When it isfound that, due to the stimulation therapy, the user's glucose levelsare gravitating towards normal levels the Health Management applicationcommunicates this information to the user's insulin pump to slow theinsulin delivery/infusion. As discussed earlier, the stimulationprotocol may be adjusted to mild or intense depending upon the effect onthe glucose levels of the user.

In some embodiments, the neuro-stimulation device of the presentspecification is sized in the form of a percutaneous skin patch thatcovers both of the T6 and T7 dermatomes. In alternate embodiments, theuser may use a first percutaneous electro-dermal patch on the T6dermatome and a second percutaneous electro-dermal patch on the T7dermatome. In such cases, the Health Management applicationalternatingly stimulates the T6 and T7 dermatomes to treat conditions ofobesity, over-weight, eating disorders, metabolic syndrome as well asT2DM. In some embodiments, the neuro-stimulation device of the presentspecification is sized to cover both of the C8 and T1 dermatomes (asshown in FIG. 19C). In alternate embodiments, the user may use a firstneuro-stimulation device on the C8 dermatome and a secondneuro-stimulation device on the T1 dermatome. In such cases, the HealthManagement application alternatingly stimulates the C8 and T1 dermatomesto treat conditions of obesity, over-weight, eating disorders, metabolicsyndrome. In various embodiments, a plurality of neuro-stimulationdevices of the present specification are used to cover T6, T7, C8 and/orT1 dermatomes that are simultaneously or alternatingly stimulated toconditions of obesity, over-weight, eating disorders, metabolic syndromeand/or T2DM.

It should be noted, that the various suggestions and recommendationsauto generated by the Health Management application, for initial freshstimulation protocols, patterns and parameter settings as well as thoserelated to adjusting these stimulation protocols and settings may, invarious embodiments, be implemented by the user only after an approvaland advice from the remote patient care facility and/or personnel. Insome embodiments, however, prior approval from the remote patient carefacility or personnel may not be required. The Health Managementapplication enables the user to set an option of prior approval ordisable this option.

In some embodiments, the neuro-stimulation device is driven bystimulation algorithms having different stimulation parameters to treatconditions of obesity, over-weight, eating disorders, metabolic syndromeby first enabling the patient to lose excess weight and then maintainthe weight loss. For example, in one embodiment, the patient isstimulated with a first stimulation algorithm to induce weight loss.Once the patient has reached a target weight, the stimulation algorithmis changed to a second stimulation algorithm to maintain the weightloss. In some embodiments, the total stimulation energy per day providedby the first algorithm to induce weight loss is greater than the totalstimulation energy per day provided by the second algorithm to maintainweight loss.

Example Stimulation Protocols for Managing Habituation, Nausea,Dyspepsia, and Skin Irritation

Habituation refers to a decrease in sensory perception of a stimulusafter prolonged presentation of the stimulus. In various embodiments ofthe present specification, in order to overcome habituation, thestimulation intensity is designed to gradually increase or decreasethroughout the entire therapy session, in contrast to prior artpractices of requiring the patient to manually increase or decreaseintensity periodically during the therapy session. The presentspecification also learns the manner and frequency of the manualadjustment of the desired stimulation intensity so as to customize thestimulation parameters that modify stimulation in order to combathabituation.

In accordance with an exemplary embodiment, the stimulation intensity(comprising the pulse amplitude and/or frequency) is increased ordecreased arithmetically (that is, linearly) or geometrically (that is,exponentially) with time. It should be noted, that an increase in thestimulation intensity is always above the user's ‘sensory threshold’(which is already determined prior to stimulation sessions) and adecrease in the stimulation therapy is constrained in that thestimulation intensity is not allowed to fall below the ‘sensorythreshold’. As an example, for geometric increase or decrease, thestimulation intensity is multiplied or divided by a fixed factor perunit time. For example, the stimulation intensity may be geometricallyincreased or decreased by a factor Z, wherein Z is say 1.004 as anexample, for every minute of a therapy session. This equates to anapproximately 27% increase or decrease in stimulation intensity over a60 minute therapy session. In various embodiments, ‘Z’ comprises a 10%to 50% increase or decrease of any given parameter. In anotherembodiment, the stimulation intensity is linearly increased or decreasedby a fixed amount, such as 0.5 mA, for every minute of the therapysession. In another embodiment, the rate of increase or decrease isadjusted to account for manual changes in the stimulation intensity. Forexample, if the user decreases the stimulation intensity in the middleof the therapy session, then the automatic rate of increase may be toohigh for this user and should be decreased for subsequent therapysessions. Similarly, if the user increases the stimulation intensity inthe middle of the therapy session, then the automatic rate of increasemay be too low for this user and should be increased for subsequenttherapy sessions. In this fashion, the automatic habituationcompensation is adaptive and responsive to the user's physiology.

In further embodiments, the stimulation continuity profile may be astep-up or a step-down profile wherein the stimulation amplitude and/orfrequency may increase or decrease on a per session basis and/or thenumber of stimulation sessions per day may increase or decreasethroughout the duration of a stimulation therapy or course to combathabituation.

In various embodiments, if the user feels nausea or dyspepsia duringand/or after stimulation sessions he may provide an input to the HealthManagement application that a nausea and/or dyspepsia event occurredwhich is then automatically time stamped and stored by the application.Resultantly, the Health Management application may modify an existingstimulation protocol, for example may recommend switching the currentintense stimulation protocol to the mild stimulation protocol.Additionally or alternatively, the stimulation continuity profile may beswitched to the step-down profile. Still further, the Health Managementapplication may recommend pausing the stimulation sessions for one ormore days before restarting with a step-down stimulation protocol.

In accordance with another exemplary embodiment, the neuro-stimulationdevice of the present specification generates biphasic, symmetrical,rectangular pulses with regulated current.

This pulse waveform is charge-balanced which prevents iontophoreticbuild-up under the electrodes that can lead to skin irritation andpotential skin damage. Regulated current pulses provide more stablestimulation than regulated voltage pulses, because the stimulationcurrent is independent of the electrode-skin impedance, which typicallychanges during the course of a therapy session. In order to address awide variety of skin types and electrode quality (due to repeat use andair exposure), the maximum output voltage is 100V and the maximum outputcurrent is 50 mA. Finally, the pulse pattern is continuous stimulationwith randomly varying inter-pulse intervals such that the frequency ofstimulation has a uniform probability distribution between 50 Hz and 150Hz. Alternatively, the frequency of stimulation may have a Gaussianprobability distribution between 50 Hz and 150 Hz, or some otherprobability distribution. The benefit of providing frequency stimulationwith randomly varying inter-pulse intervals (versus frequencystimulation with constant inter-pulse intervals) is that the former typeof stimulation may lead to less nerve habituation.

Still further embodiments may involve relocating the neuro-stimulationdevice from the first stimulation spot to a second spot and alternatingbetween the first and second stimulation spots to avoid habituation,skin irritation, nausea and/or dyspepsia.

Method of Use

In accordance with various aspects of the present specification, thePEDP device is configured to be self-implanted or self-administered bythe user or implanted by a physician or medical personnel.

For self-implantation, as described earlier with reference to FIG. 1G,the user places the PEDP on the skin at an appropriate site or locationto deploy a retractable needle, included on the bottom surface of thePEDP that touches the user's skin, that punctures the skin and isthereafter retracted leaving behind an electrically conductive catheteror lumen underneath the skin. In accordance with another embodiment, forself-implantation by the user, the one or more electrodes (such as theone or more electrodes 118 of FIG. 1A, for example) are configured as anarray of micro-needles that enable a patient-friendly intradermalstimulation delivery solution as described earlier with reference toFIG. 1H.

In accordance with another aspect, the PEDP of the present specificationis implanted by a physician or medical personnel using a percutaneouselectrode insertion system (such as the system 230 described earlierwith reference to FIG. 2C).

In accordance with some embodiments, for self-implantation of the PEDP,the user is enabled to apply or use the neuro-stimulation device of thepresent specification with no or minimal intervention from a physician.In some embodiments, the user visits his physician for just one sessionwherein, depending upon the user's medical condition, the physician mayprescribe the neuro-stimulation device of the present specification tothe user along with the stimulation depth configuration, from 0.1 mm to60 mm, and preferably 0.1 mm to 30 mm of the dermis, of theneuro-stimulation device, as described with reference to FIG. 1A through1F. In various embodiments, a stimulation depth through the patient'sepidermal layer ranges from 0.1 mm, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, to 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 orany increment therein. During the session, the physician instructs theuser in identifying appropriate areas of stimulation, such as T6, C8and/or T1 dermatomes for conditions of obesity, over-weight, eatingdisorders, metabolic syndrome and T7 for T2DM management, and alsoprovides an orientation to the user regarding use and functions of theneuro-stimulation device. In various embodiments, the appropriate areasof stimulation may be identified, for example, by one or more temporarytattoos (such as a small dot) or an image of the user may be taken witha mark or icon locating the appropriate area on the user's body. Duringthe session, the physician may further help the user to download theHealth Management application on the user's computing device, such ashis smartphone, tablet, PDA, laptop, computer and demonstrate pairing orsyncing of the application to the user's computing device. The user mayat this time or at a later time enable the Health Management applicationto be in communication with the physician or a remote patient carefacility.

In various embodiments, therapy provided by the percutaneouselectro-dermal patch (PEDP) devices of the present specification isdriven or triggered by a plurality of variables. These variables can beentered by the patient or a medical professional into the companiondevice, sensed by a sensor on the PEDP, transmitted to the companiondevice or PEDP by a separate device, for example, a device, withphysiological sensors, configured to be worn on the human body, such asaround the wrist, in order to monitor, acquire, record, and/or transmitthe physiological data, or can be acquired by a combination of any ofthe above means. In various embodiments, the variables are stored,preset, and/or measured or input on a regular, predetermined basis ortime period. In some embodiments, the variables include primaryvariables which comprise primary drivers to any therapy regimen andsecondary variables which comprise secondary indicators which may or maynot affect the regimen. Some variables, such as weight in pounds, areentered into the patient diary based on their actual value while othervariables, such as hunger, appetite and satiety, are given a score basedon a predefined score value range or a scale such as the Visual AnalogueScale (VAS). The treatment algorithm of the companion device analyzesthese scores in comparison to predefined limits and automaticallymodifies therapy accordingly. In some embodiments, the algorithmanalyzes these scores on a daily basis. In other embodiments, thealgorithm analyzes the scores every other day, every third day, everyfourth day, every fifth day, every sixth day, or once per week. Invarious embodiments, the score values range from 0 to 100. In apreferred embodiment, the score values range from 1 to 10 and, morepreferably, from 1 to 5 or 1 to 3, depending on the variable. In someembodiments, a high numerical score value indicates electricalstimulation therapy provided by the PEDP is inadequate and additionalstimulation is needed. A lower numerical score value indicateselectrical stimulation therapy provided by the PEDP is excessive andstimulation needs to be reduced. Conversely, in other embodiments, ahigh numerical score value indicates stimulation is excessive and needsto be reduced and a low numerical score value indicates stimulation isinadequate and needs to be increased. In some embodiments, a numericalscore value proximate the middle of the score range indicates therapy isappropriate and can remain unchanged.

In one embodiment, the system uses one or more of the following triggersto initiate stimulation or modulate stimulation settings: a patient'sglycemic level, metabolism levels, hemoglobin A1c, and/or blood sugar.Using physiological sensors or external devices which already measuremetabolism, blood sugar, glycemic levels, or hemoglobin A1c, thecompanion device gathers such data, integrates it with existing patientstatus data, and generates a modulated stimulation setting, which mayinclude a signal to initiate therapy, change therapy or cease therapy,based on an integrated patient status data profile. In one embodiment, apatient's increased blood sugar levels cause the stimulation settings tobe modulated upward in order to increase the rate, frequency, or overallamount of stimulation. In another embodiment, changes in the patientstatus data, including increases or decreases in metabolism, bloodsugar, glycemic levels, or hemoglobin A1c, may cause the companiondevice to recommend moving the PEDP to a different location on thepatient's body to stimulate a different dermatome, such as from C8 onthe hand to T1 or, for example, from T7 in the abdominal area to T6.

In some embodiments, therapy is driven by a set of three primarydrivers. The primary drivers include: hunger, which is defined as thepatient's desire to eat; appetite, defined as how much food the patienteats in relation to a diet plan (also considered caloric intake); andwell-being, defined as simply how good the patient feels. In someembodiments, well-being is further subdivided specifically into feelingsof nausea, dyspepsia, discomfort, energy level, and weakness/strength.Each of these primary drivers can be attributed a score which is enteredinto the companion device, as depicted in FIGS. 11, 13, and 16.

For example, for hunger, referring to FIG. 13, the patient can enter ahunger score from 1 to 5, wherein 1 indicates the patient is not hungryat all, 2 indicates the patient is almost never hungry, 3 indicates thepatient is not particularly hungry, 4 indicates the patient isfrequently hungry, and 5 indicates the patient is extremely hungry mostof the time. In some embodiments, a hunger score having a highernumerical value indicates appetite suppression is inadequate and thepatient requires greater stimulation. The treatment algorithm of thecompanion device recognizes the need for greater stimulation asindicated by the higher score and titrates therapy accordingly. Forexample, in one embodiment, if the patient enters a hunger score greaterthan 3 in the patient diary over a period of four to seven consecutivedays within the first week, the algorithm uses the score toincrementally increase the duration of each stimulation session. Ifafter three weeks the patient enters a hunger score greater than 3 inthe patient diary for 3 consecutive days, the algorithm uses the scoreto increase the number of stimulation sessions per day. Conversely, alower hunger score indicates stimulation needs to be decreased. Forexample, if the patient enters a hunger score of 1 for three consecutivedays within the first week, stimulation sessions are decreased induration and frequency. In other embodiments, the hunger score scaleextends from 1 to 10.

In other embodiments, rather than a scale to determine the presence orabsence of hunger, the system presents the patient with a scaleconfigured to record changes in his hunger after stimulation. Forexample, in an embodiment, a hunger change score scale extends from 1 to3 wherein 1 is indicative of no change, 2 is indicative of some change,and 3 is indicative of significant change in hunger after stimulation.If a patient reports a 1, no change in hunger after stimulation,stimulation parameters are increased.

For appetite, referring to FIG. 11, the patient can enter an appetitescore from 1 to 5, wherein 1 indicates the patient ate substantiallyless than his diet, 2 indicates the patient ate a little less than hisdiet, 3 indicates the patient followed his diet, 4 indicates the patientsomewhat exceeded his diet, and 5 indicates the patient substantiallyexceeded his diet. As with the hunger score discussed above, in someembodiments, an appetite score having a higher numerical value indicatesappetite suppression is inadequate and the patient requires greaterstimulation. The treatment algorithm of the companion device recognizesthe need for greater stimulation as indicated by the higher score andtitrates therapy accordingly. For example, in one embodiment, if thepatient enters an appetite score greater than 3 in the patient diaryover a period of four to seven consecutive days within the first week,the algorithm uses the score to incrementally increase the duration ofeach stimulation session. If after three weeks the patient enters anappetite score greater than 3 in the patient diary for 3 consecutivedays, the algorithm uses the score to increase the number of stimulationsessions per day. Conversely, a lower appetite score indicatesstimulation needs to be decreased. For example, if the patient enters anappetite score of 1 for three consecutive days within the first week,stimulation sessions are decreased in duration and frequency. In otherembodiments, the appetite scale extends from 1 to 10.

As discussed earlier, in some embodiments the plurality of variables,such as hunger, appetite, satiation level, fullness, satiety, andfeelings of pain, nausea, or dyspepsia, that drive or trigger therapyare alternately assessed on at least one of a plurality of scientificVAS scales. Graphs 30A through 32F represent exemplary data which theinventors believe are indicative of the therapeutic benefits of thepresent inventions. It should be appreciated that data may be collectedand compared on a per patient basis, both before and after stimulation,on a sample group of patients, both before and after stimulation, or byusing two separate groups of patients, one subjected to stimulation andthe other not subjected to stimulation (as a control). Therefore thepost-stimulation benefits would be achieved regardless of whether onewere comparing it to the same population of users before stimulation orto a different population of users acting as a control group.

FIGS. 30A through 30I are a set of graphs illustrating effects ofstimulation on a feeling of hunger as assessed on a VAS (Visual AnalogueScale) in accordance with some embodiments, while FIGS. 37A through 37Iare a set of graphs illustrating effects of stimulation on a feeling ofsatiety as assessed on a VAS in accordance with some embodiments.Referring to FIGS. 30A through 30E, in accordance with an embodiment, asample of 5 patients, having weight loss as an objective or goal, wereassessed for their feeling of hunger (using VAS) at a first occasion,corresponding to a pre-stimulation scenario wherein the 5 patients werenot subjected to stimulation therapy, and at a second occasion,corresponding to a post-stimulation scenario wherein the 5 patients weresubjected to stimulation therapy using a PEDP of the presentspecification.

In accordance with an embodiment, the 5 patients were assessed both pre-and post-stimulation using a VAS hunger questionnaire, such as thequestionnaire of FIG. 35A, having a 100 mm VAS line. At the firstoccasion (pre-stimulation), each patient's responses or scores to theVAS hunger questionnaire were recorded at intervals of every 60 minutesstarting from a first response or score 3006 a through 3006 e that, inone embodiment, is recorded just prior to a meal (such as breakfast) butwithout subjecting any of the patients to stimulation therapy. At thesecond occasion (post-stimulation), each patient's responses or scoresto the VAS hunger questionnaire were again recorded at intervals ofevery 60 minutes starting from a first response or score 3007 a through3007 e recorded just prior to the meal (such as breakfast) but afterhaving treated each of the patients with stimulation therapy prior to,for example 30 minutes before, the meal. In accordance with anembodiment, the responses or scores related to the first occasion arerecorded on a first day while those related to the second occasion arerecorded on a second day, preferably at the same time of day and underthe same eating or fasting conditions as the first day.

As shown in FIG. 30A, the first patient's hunger responses or scores forthe first occasion (that is, pre-stimulation) are recorded on a firstday and plotted on a graph, whose x-axis represents time in minutes andy-axis represents VAS hunger responses or scores in millimeters, togenerate a pre-stimulation hunger profile 3005 a. Thereafter, the firstpatient is subjected to stimulation therapy, in accordance toembodiments of the present specification, and the hunger responses orscores for the second occasion (that is, post-stimulation) are alsoplotted on the graph to generate a post-stimulation hunger profile 3008a. Similarly, the second, third, fourth and fifth patients' responses orscores are recorded to generate the respective pre-stimulation hungerprofiles 3005 b, 3005 c, 3005 d, 3005 e and the respectivepost-stimulation hunger profiles 3008 b, 3008 c, 3008 d, 3008 e as shownin FIGS. 30B through 30E. As can be observed from FIGS. 30A through 30E,the post-stimulation huger profiles 3008 a, 3008 b, 3008 c, 3008 d, 3008e reflect reduced hunger magnitude relative to the pre-stimulationhunger profiles 3005 a, 3005 b, 3005 c, 3005 d, 3005 e. In someembodiments, the post-stimulation hunger profile of a patient reflectsat least a 5% decrease in hunger magnitude relative to the patient'spre-stimulation hunger profile.

FIG. 30F shows a first bar 3010 representing a median area under curve(AUC) pre-stimulation hunger score. An AUC value is determined bycalculating the area under the lines which define a given plottedprofile. A second bar 3011 represents a median AUC end-of-stimulationhunger score derived from AUC values for end-of-stimulation hungerprofiles (that is, the hunger profiles recorded starting immediatelyafter the end of stimulation therapy) of the sample patients, and athird bar 3012 represents a median AUC post-stimulation hunger scorederived from AUC values for post-stimulation hunger profiles of thesample patients. In various embodiments, end-of-stimulation is definedas the end of a period of stimulation lasting in a range from onesession to a multitude of sessions over six months. In variousembodiments, post-stimulation is defined as a time after the cessationof therapy and ranges from one day after cessation to six months aftercessation. As shown in the figure, the median AUC hunger scores 3011,3012 corresponding to end-of-stimulation and post-stimulation scenariosare reduced relative to the median AUC hunger score 3010 correspondingto the pre-stimulation scenario. In other words, the stimulation therapyof the present specification results in hunger suppression. In someembodiments, an area under the curve (AUC) of the post-stimulationhunger profile of a patient reflects at least a 5% decrease relative tothe patient's AUC of the pre-stimulation hunger profile.

FIGS. 30G and 30H also illustrate reduced magnitude of hunger scores,for at least one patient, assessed post stimulation relative to thoseassessed pre-stimulation. FIGS. 30G and 30H are charts having x-axisrepresenting time in weeks and y-axis representing hunger scores. FIG.30G shows a pre-stimulation hunger profile 3015 g relative to apost-stimulation hunger profile 3016 g over extended period of timessuch as, in weeks and up to 32 weeks. Similarly, FIG. 30H also shows apre-stimulation hunger profile 3015 h relative to a post-stimulationhunger profile 3016 h over the same extended period of times. As can beobserved from the FIGS. 30G and 30H, the post-stimulation hungerprofiles 3016 g, 3016 h show reduced hunger AUC and magnitude relativeto the respective pre-stimulation hunger profiles 3015 g, 3015 h, evenover extended periods of time.

FIG. 30I is another graph showing a first median or average hunger score3020 (assessed using the VAS hunger questionnaire, such as that of FIG.29A) recorded on a first day prior to subjecting one or more patients tostimulation therapy (pre-stimulation scenario), a second median oraverage hunger score 3622 recorded at the end of subjecting one or morepatients to stimulation therapy (end-of-stimulation scenario) and athird median or average hunger score 3624 recorded on a second day afterhaving subjected one or more patients to stimulation therapy(post-stimulation scenario).

Referring now to FIGS. 31A through 31E, in accordance with anembodiment, a sample of 5 patients, having weight loss as an objectiveor goal, were assessed for their feeling of satiety (using VAS) at afirst occasion, corresponding to a pre-stimulation scenario wherein the5 patients were not subjected to stimulation therapy and at a secondoccasion, corresponding to a post-stimulation scenario wherein the 5patient were subjected to stimulation therapy using a PEDP of thepresent specification.

In accordance with an embodiment, the 5 patients were assessed both preand post stimulation using a VAS satiety questionnaire, such as thequestionnaire of FIG. 29D, having a 100 mm VAS line. At the firstoccasion (pre-stimulation), each patient's responses or scores to theVAS satiety questionnaire were recorded at intervals of every 60 minutesstarting from a first response or score 3106 a through 3106 e that, inone embodiment, is recorded just prior to a meal (such as breakfast) butwithout subjecting any of the patients to stimulation therapy. At thesecond occasion (post-stimulation), each patient's responses or scoresto the VAS satiety questionnaire were again recorded at intervals ofevery 60 minutes starting from a first response or score 3107 a through3107 e recorded just prior to the meal (such as breakfast) but afterhaving treated each of the patients with stimulation therapy prior to,for example 30 minutes before, the meal. In accordance with anembodiment, the responses or scores related to the first occasion arerecorded on a first day while those related to the second occasion arerecorded on a second day, preferably at the same time of day and underthe same eating or fasting conditions as the first day.

As shown in FIG. 31A, the first patient's satiety responses or scoresfor the first occasion (that is, pre-stimulation) are recorded on afirst day and plotted on a graph, whose x-axis represents time inminutes and y-axis represents VAS satiety responses or scores inmillimeters, to generate a pre-stimulation satiety profile 3105 a.Thereafter, the first patient is subjected to stimulation therapy, inaccordance to embodiments of the present specification, and the satietyresponses or scores for the second occasion (that is, post-stimulation)are also plotted on the graph to generate a post-stimulation satietyprofile 3108 a. Similarly, the second, third, fourth and fifth patients'responses or scores are recorded to generate the respectivepre-stimulation satiety profiles 3105 b, 3105 c, 3105 d, 3105 e and therespective post-stimulation satiety profiles 3108 b, 3108 c, 3108 d,3108 e as shown in FIGS. 31B through 31E. As can be observed from FIGS.31A through 31E, the post-stimulation satiety profiles 3108 a, 3108 b,3108 c, 3108 d, 3108 e reflect reduced satiety magnitude relative to thepre-stimulation satiety profiles 3105 a, 3105 b, 3105 c, 3105 d, 3105 e.In some embodiments, the post-stimulation satiety profile of a patientreflects at least a 5% increase in satiety magnitude relative to thepatient's pre-stimulation satiety profile.

FIG. 31F shows a first bar 3110 representing a median AUCpre-stimulation satiety score derived from AUC values forpre-stimulation satiety profiles of at least one patient, a second bar3111 representing a median AUC end-of-stimulation satiety score derivedfrom AUC values for end-of-stimulation satiety profiles (that is, thesatiety profiles recorded starting immediately after the end ofstimulation therapy) of the at least one patient and third bar 3112representing a median AUC post-stimulation satiety score derived fromAUC values for post-stimulation satiety profiles of the at least onepatient. In various embodiments, end-of-stimulation is defined as theend of a period of stimulation lasting in a range from one session to amultitude of sessions over six months. In various embodiments,post-stimulation is defined as a time after the cessation of therapy andranges from one day after cessation to six months after cessation. Asshown in the figure, the median AUC satiety scores 3111, 3112corresponding to end-of-stimulation and post-stimulation scenarios areelevated or improved relative to the median AUC satiety score 3110corresponding to the pre-stimulation scenario. In other words, thestimulation therapy of the present specification results in hungersuppression or improved satiety. In some embodiments, an area under thecurve (AUC) of the post-stimulation satiety profile of a patientreflects at least a 5% increase relative to the patient's AUC of thepre-stimulation satiety profile.

FIGS. 31G and 31H also illustrate reduced magnitude of satiety scores,for at least one patient, assessed post stimulation relative to thoseassessed pre-stimulation. FIGS. 31G and 31H are charts having x-axisrepresenting time in weeks and y-axis representing satiety scores. FIG.31G shows a pre-stimulation satiety profile 3115 g relative to apost-stimulation satiety profile 3116 g over extended period of timessuch as, in weeks and up to 32 weeks. Similarly, FIG. 31H also shows apre-stimulation satiety profile 3115 h relative to a post-stimulationsatiety profile 3116 h over the same extended periods of time. As can beobserved from the FIGS. 31G and 31H, the post-stimulation satietyprofiles 3116 g, 3116 h show improved or increased satiety AUC andmagnitude relative to the respective pre-stimulation satiety profiles3115 g, 3115 h, even over extended periods of time.

FIG. 31I is another graph showing a first median or average satietyscore 3120 (assessed using the VAS hunger questionnaire, such as that ofFIG. 29D) recorded on a first day prior to subjecting the at least onepatient to stimulation therapy (pre-stimulation scenario), a secondmedian or average satiety score 3122 recorded at the end of subjectingthe at least one patient to stimulation therapy (end-of-stimulationscenario) and a third median or average satiety score 3124 recorded on asecond day after having subjected the at least one patient tostimulation therapy (post-stimulation scenario).

It should be appreciated that while FIGS. 36A through 36I illustrate preand post hunger levels and FIGS. 31A through 31I illustrate pre and postsatiety levels, in various embodiments, various patient sensations suchas satiation and fullness are also similarly assessed and recorded usingVAS under pre and post stimulation scenarios. It should also beappreciated that the pre-stimulation levels of a patient sensations,such as hunger, appetite, satiety, satiation and fullness, are measuredusing a scale (such as a VAS) at predefined times of day over a firstpredefined period of time, and the post-stimulation levels of thepatient sensations are measured, after stimulation is initiated, usingthe scale at the predefined times of day over a second predefined periodof time, equal in duration to the first predefined period of time. Inaddition, in various embodiments, a patient's change in satiety, definedas an alteration in the patient's perception of gastric fullness oremptiness, is measured using a scale (such as a VAS) to determineefficacy of therapy provided by a PEDP device. Further, in variousembodiments, the results obtained by the VAS, not only for change insatiety but for all patient sensations, are used to modify stimulationprovided by the PEDP device.

For well-being, in one embodiment and referring to FIG. 16, the patientcan enter a score from 1 to 3, wherein 1 indicates no nausea/abdominaldiscomfort, 2 indicates occasional nausea/abdominal discomfort, and 3indicates the patient is experiencing frequent nausea/abdominaldiscomfort. In some embodiments, for well-being, a higher scoreindicates stimulation is too intense, causing the patient to experiencenausea, and that a reduction in stimulation is needed. The treatmentalgorithm of the companion device recognizes the need for reducedstimulation as indicated by the higher score and titrates therapyaccordingly. For example, in one embodiment, if the patient enters awell-being score of 3 in the patient diary for three consecutive days,the algorithm uses the score to incrementally reduce the number ofstimulation sessions per day or week and/or the length of eachstimulation session. In one embodiment, parameter modifications based onwell-being scores supersede those based on hunger and/or appetitescores. These primary drivers are tracked to determine how best tomodify stimulation on an on-going basis to provide the patient with theproper amount of stimulation such that the patient does not experiencefeelings of nausea, dyspepsia, does not experience low energy orweakness, and does not have too large an appetite or consume too muchfood. The tracking of these variables allows for automatic modificationof stimulation parameters, based on predefined variable ranges andlimits, to provide the patient with a therapeutic stimulation protocolwithout the need of constant management by the patient.

In some embodiments, therapy is further driven by a set of two secondaryindicators. The secondary indicators include patient weight and caloriesexpended/exercise. Weight can be entered in pounds and caloriesexpended/exercises can be attributed a score which is entered into thecompanion device, as depicted in FIGS. 12 and 15. For example, forweight, referring to FIG. 15, the patient can enter his weight in poundsusing a keypad on the companion device. In one embodiment, the patiententers his weight in the patient diary on a weekly basis. In otherembodiments, the companion device is configured to communicatewirelessly with a wireless scale (i.e. bathroom scale) such that thepatient's weight is automatically entered into the companion device whenthe patient weighs himself on the scale. This improves system accuracyby eliminating the possibility of the patient entering an incorrectweight. In addition, the system can track how often and when the patientweighs himself, send reminders, and titrate therapy based on thecommunicated weight. In another embodiment, the companion device isconfigured to communicate wirelessly with a separate body fat measuringdevice. As with the patient's weight, automatic transmission ofcalculated body fat to the companion device results in improved systemaccuracy, body fat measuring tracking and reminders, and therapytitration based on communicated body fat data. In various embodiments,the companion device is configured to communicate wirelessly with aseparate device capable of measuring a plurality of physiologicalparameters, including, but not limited to, patient weight, body fat,lean mass, and body mass index (BMI). Data from these parameters isautomatically input into a treatment algorithm of the companion deviceand is used to drive therapy by modifying electrical stimulationparameters.

For calories expended/exercise, referring to FIG. 12, the patient canenter an exercise score from 1 to 5, wherein 1 indicates the patienttook more than 10,000 steps in a single day, 2 indicates the patienttook 7,500-10,000 steps in a single day, 3 indicates the patient took5,000-7,500 steps in a single day, 4 indicates the patient took2,500-5,000 steps in a single day, and 5 indicates the patient took lessthan 2,500 steps in a single day. In some embodiments, the secondaryindicators further include fitness input (from a separate device, forexample, a device, with physiological sensors, configured to be worn onthe human body, such as around the wrist, in order to monitor, acquire,record, and/or transmit the physiological data) and biological inputs(such as ghrelin levels).

Similar to the primary drivers, these secondary indicators can betracked to determine how best to modify stimulation on an on-going basisto provide the patient with the proper amount of stimulation. In someembodiments, the secondary indicators possess less value compared to theprimary drivers in determining how best to modify the PEDP stimulationparameters. Although embodiments having three primary drivers and twosecondary indicators have been discussed, additional embodiments havinggreater or fewer primary drivers and/or secondary indicators arepossible and the variables presented are not intended to be limiting.

The PEDP devices of the present specification can be used to enable apatient to comply with a dietary plan. In some embodiments, the systemcalculates, for example, via an application or software on themicroprocessor of the PEDP, the timing of food consumption by thepatient, the total calories consumed, and the type of food consumed(i.e. glycemic index, carbohydrate profile, and protein profile). Thesystem then, via an algorithm through said application or software, usesthe calculated information to titrate electrical stimulation therapy.For example, if the patient eats outside his normal dietary time, eatstoo many calories based on his diet, and/or eats foods high in glycemicindex or carbohydrate profile, the system recognizes this and increasesany one or combination of stimulation amplitude, frequency, number ofsessions, session length, or session timing.

Specifically, in various embodiments, the system calculates timing ofconsumption, total calories consumed, and type of food consumed, asdescribed above, along with other parameters such as exercise andon-going weight loss, and, based on the calculations, performs thefollowing therapy adjustments:

-   -   If a patient consumes too many calories, based on his dietary        plan, over a predetermined period (for example, 3 days), the        stimulation duration, intensity, and/or number of sessions is        increased.    -   If a patient consumes too much food at a specific time of day        each day over a predetermined period (for example, 3 days), the        timing of stimulation is changed to prior to (for example, a        half hour or 1 hour before) the overeating time and/or an        additional stimulation session is added prior to the overeating        time.    -   If a patient consumes foods outside his dietary plan, for        example, too many carbohydrates, over a predetermined period        (for example, 3 days), the stimulation duration, intensity,        session timing, and/or number of sessions is increased.    -   If a patient stops exercising for a predetermined period (for        example, 3 days), stimulation parameters are increased.    -   If, following a course of treatment, the patient has lost a        predetermined amount of target weight, the system algorithm        decreases stimulation parameters, in some embodiments either by        a physician or via a downloadable application.

For some patients, compliance becomes easier when the patient does notneed to track the amount of calories in each piece of food consumed butrather is presented with a dietary plan with a listing of foods whereinthe calorie profile of each item of food is already known. Therefore, insome embodiments, the system provides the patient with a number ofbreakfast, lunch, dinner, and optionally snack meal plans from which tochoose. The calorie profile of each of these meal plans ispre-calculated. These calorie profiles are pre-programmed into thesoftware or applications of the PEDP device. Patients no longer need totrack the calorie content of each item of food consumed but can simplyreport how well they are complying with the chosen meal plans. Further,in some embodiments, the PEDP can be linked to a separate wearabledevice, for example, a device, with physiological sensors, configured tobe worn on the human body, such as around the wrist, in order tomonitor, acquire, record, and/or transmit physiological data, such asexercise data, to the PEDP so that calories expended, as tracked by theseparate device, are deducted from calories consumed, as per thespecific meal plans, to provide the patient and system with caloriebalance information.

In some embodiments, patients are instructed to follow a 1200calorie/day diet plan. Based on the above, too many calories consumedabove the baseline 1200 and/or the wrong calories consumed (for example,a bad glycemic index, too many sugars consumed, and/or too manycarbohydrates consumed) will result in an increase in stimulation. Ifpoor eating habits (for example, too many of the wrong calories) areconcentrated at a particular time of day, the system adjusts to add asession just prior to the particular time to lower hunger and improveeating behavior.

In some embodiments, stimulation is programmed to begin before (forexample, 1 week prior to) the patient starts on his dietary plan.Beginning stimulation before the patient changes to a new dietary planreduces the patient's appetite before the change in eating and resultsin better compliance as patients are less likely to become disheartenedif they stray from their diet due to high hunger levels. In otherembodiments, patients only receive stimulation therapy and do not go ona dietary plan.

FIG. 21C is a flow chart illustrating the steps involved in oneembodiment of a method of using an neuro-stimulation device to suppressappetite in a patient. At step 2102, a patient obtains a percutaneouselectro-dermal patch (PEDP) device, in accordance with the devicesdisclosed in the present specification, from a medical professional.

The PEDP device is set into a default operational mode, either by thepatient or by the medical professional, at step 2104. In someembodiments, the default operational mode includes the followingstimulation parameters and parameter ranges: pulse width in a range of10 μsec to 10 msec; pulse amplitude in a range of 100 μA to 500 mA;pulse frequency in a range of 1 Hz to 10,000 Hz; pulse duty cycle in arange of 1% to 100%; session duration in a range of 1 min to 120 min orsubstantially continuously; and 1 to 24 sessions per day. In a preferredembodiment, the default operational mode includes the followingstimulation parameters: pulse width equal to 200 μsec; pulse amplitudeequal to 5 mA; pulse frequency equal to 20 Hz; pulse duty cycle equaling100%; session duration equaling 30 minutes; and 1 session per day. Then,at step 2106, the PEDP device is positioned on the patient's body, suchthat the at least one electrode can be implanted just underneath thepatient's skin. In various embodiments, the PEDP device is eitherself-implanted by the patient himself or is implanted by a physician ormedical personnel. The patient is allowed to modify the defaultoperational mode within a set of predefined ranges at step 2108. Thepatient may modify the default operational mode based upon patientfeedback or feedback provided by a separate wearable device, forexample, a device, with physiological sensors, configured to be worn onthe human body, such as around the wrist, in order to monitor, acquire,record, and/or transmit the physiological data. At step 2110, the PEDPdevice displays appetite, stimulation sessions, caloric intake, andpatient weight in a variety of graphical user interfaces (GUIs). Otherparameters may also be listed, and the list in step 2110 is not intendedto be limiting. The PEDP device forces or allows, through patient input,changes to the operational mode in the case of nausea, dyspepsia orhabituation or to conserve battery at step 2112. The PEDP device forcesthe changes when feedback data provided by the device or anotherwearable device falls outside preset ranges indicating habituation isoccurring. In some embodiments, habituation occurs when hunger returnsover time despite electrical stimulation via the stimulation protocolsdisclosed in the present specification.

The return of hunger indicates a loss of appetite suppression due tohabituation of the patient to the electrical stimulation. The patientmay change the operational mode if he or she is experiencing nauseaand/or dyspepsia.

FIG. 22 is a flow chart illustrating the steps involved in anotherembodiment of a method of using an neuro-stimulation device to suppressappetite in a patient. At step 2202, a patient obtains a percutaneouselectro-dermal patch (PEDP) device, in accordance with the devicesdisclosed in the present specification, from a medical professional. ThePEDP device is set into a default operational mode, either by thepatient or by the medical professional, at step 2204. In variousembodiments, the default operational mode includes the stimulationparameters and parameter ranges listed above with respect to FIG. 21C.Then, at step 2206, the PEDP device is implanted just underneath theskin of the patient by a medical professional or self-implanted by theuser himself. The PEDP device automatically modifies the defaultoperational mode based upon predetermined triggers at step 2208. Invarious embodiments, the triggers include, but are not limited to,patient diary recording of appetite, hunger, and well-being, and datafrom a separate device, with physiological sensors, configured to beworn on the human body, such as around the wrist, in order to monitor,acquire, record, and/or transmit the physiological data, datatransmitted to the companion device. For example, in one embodiment, thepatient records an appetite diary entry with a score of 5, wherein thepatient substantially exceeded his diet during his most recent meal,indicative of dietary non-compliance (that is, not conforming to a dietplan) or poor dietary compliance. In some embodiments, one or morescores of 5 on appetite triggers the companion device to automaticallyincrease therapy parameters, for example, an increase in stimulationintensity, duration, or sessions.

In another embodiment, for example, the patient records a hunger diaryentry with a score of 1, wherein the patient experienced no hunger atall at his most recent meal time. In some embodiments, one or morescores of 1 on hunger triggers the companion device to automaticallydecrease therapy parameters, for example, a decrease in stimulationintensity, duration, or sessions. At step 2210, the PEDP device displaysappetite, stimulation sessions, caloric intake, and patient weight in avariety of graphical user interfaces (GUIs). Other parameters may alsobe listed, and the list in step 2210 is not intended to be limiting. ThePEDP device then follows a ramp down procedure, wherein stimulationparameters are decreased sequentially, to conserve battery and avoidpotential habituation at step 2212.

FIG. 23 is a flow chart illustrating the steps involved in anotherembodiment of a method of using an neuro-stimulation device to suppressappetite in a patient. At step 2302, a patient obtains a percutaneouselectro-dermal patch (PEDP) device, in accordance with the devicesdisclosed in the present specification, from a medical professional. ThePEDP device is set into a default operational mode, either by thepatient or by the medical professional, at step 2304. In variousembodiments, the default operational mode includes the stimulationparameters and parameter ranges listed above with respect to FIG. 21C.Then, at step 2306, the PEDP device is implanted within the patient'sbody by a medical professional or self-implanted by the user himself.The PEDP device automatically modifies the default operational modeafter a predefined number of days of a patient diary record of appetiteor hunger at step 2308. In various embodiments, the predefined number ofdays is in a range of 1 to 7 days. In one embodiment, the predefinednumber of days is 3 days. In one embodiment, in combination with step2308, the PEDP device allows the patient to manually adjust stimulationparameters to address nausea, dyspepsia or provide an emergencystimulation to address hunger at step 2310. At step 2312, the PEDPdevice displays appetite, stimulation sessions, caloric intake, andpatient weight in a variety of graphical user interfaces (GUIs). Otherparameters may also be listed, and the list in step 2312 is not intendedto be limiting. The PEDP device then follows a ramp down procedure,wherein stimulation parameters are decreased sequentially, to conservebattery and avoid potential habituation at step 2314.

FIG. 24 is a flow chart illustrating the steps involved in anotherembodiment of a method of using an neuro-stimulation device to suppressappetite in a patient. At step 2402, a patient obtains a percutaneouselectro-dermal patch (PEDP) device, in accordance with the devicesdisclosed in the present specification, from a medical professional. ThePEDP device is set into a default operational mode, either by thepatient or by the medical professional, at step 2404. In variousembodiments, the default operational mode includes the stimulationparameters and parameter ranges listed above with respect to FIG. 21C.Then, at step 2406, the PEDP device is implanted within the patient'sbody by a medical professional or self-implanted by the user himself.The PEDP device automatically modifies the default operational modeafter a predefined amount of calorie consumption or calories burned, asdetermined by diary entries or information gathered from a separatedevice, or after a predefined number of days of weight data has beenrecorded at step 2408. In various embodiments, the predefined number ofdays is in a range of 1 to 7 days. In one embodiment, the predefinednumber of days is 3 days. In one embodiment, in combination with step2408, the PEDP device allows the patient to manually adjust stimulationparameters to address nausea, dyspepsia or provide an emergencystimulation to address hunger at step 2410. At step 2412, the PEDPdevice displays appetite, stimulation sessions, caloric intake, andpatient weight in a variety of graphical user interfaces (GUIs). Otherparameters may also be listed, and the list in step 2412 is not intendedto be limiting. The PEDP device then follows a ramp down procedure,wherein stimulation parameters are decreased sequentially, to conservebattery and avoid potential habituation at step 2414.

FIG. 25 is a flow chart illustrating the steps involved in yet anotherembodiment of a method of using an neuro-stimulation device to suppressappetite in a patient. At step 2502, the patient obtains a percutaneouselectro-dermal patch (PEDP) device and pairs the EPD device with acompanion device, such as a smartphone, and a separate device, forexample, a device, with physiological sensors, configured to be worn onthe human body, such as around the wrist, in order to monitor, acquire,record, and/or transmit the physiological data. In some embodiments,pairing with the separate device can be done anytime within a treatmentcycle. In some embodiments, a treatment cycle lasts 3 months. At step2504, the device is set into a default operational mode. In someembodiments, the default operational mode includes the stimulationparameters and parameter ranges listed above with respect to FIG. 21Cand includes daily stimulation.

The PEDP device is implanted within the patient's body at step 2506 by amedical professional or self-implanted by the user himself. At step2508, the companion device accumulates patient variable data, including,but not limited to, appetite, hunger, well-being, weight, and caloriesexpended/weight loss, in a patient diary over a predefined period oftime. In some embodiments, the companion device accumulates data over arange of 1 to 7 days. In one embodiment, the companion deviceaccumulates data for 3 days. Then, at step 2510, the companion devicedrives stimulation therapy wirelessly through the PEDP device based onaccumulated patient diary data over the treatment cycle. During thetreatment cycle, if the patient experiences nausea and/or dyspepsia, thecompanion device ramps down stimulation parameters quickly at step 2512.During the treatment cycle, if the patient experiences satiety, definedas the absence of hunger coupled with good dietary compliance, thecompanion device slowly lowers stimulation to a minimum threshold, suchas one 15 minute stimulation session every other day, to preservebattery and prevent habituation, or leaves stimulation unchanged at step2514. During the treatment cycle, if the patient experiences hunger isdietary non-compliant, the companion device ramps up stimulationaccordingly at step 2516. At step 2518, the companion device modifiesstimulation based upon actual weight loss, measured ghrelin levels, orestimated calories expended during the treatment cycle. In oneembodiment, the companion device uses a weight loss predictor algorithmbased on caloric input versus caloric consumption. At step 2520, thecompanion device displays a composite score measuring overall successderived from the variable inputs. If the patient is non-compliant, thecompanion device will provide audible and/or visual reminders to thepatient at step 2522. Optionally, at step 2524, the companion deviceprovides the patient with the option of sharing his results via socialmedia with designated friends and family.

In an alternate embodiment, the companion device first accumulatespatient diary data before the PEDP device is set into the defaultoperation mode. Referring to FIG. 25, in this alternate embodiment, step2508 is performed prior to step 2504. The remaining steps proceed in thesame order.

In other embodiments, a patient is provided with manual options ofoperating the PEDP device. The patient may operate the device at low,medium, and high settings, based on the patient variable data. Forexample, in one embodiment, a patient starts the PEDP device at a highsetting but begins to experience nausea and/or dyspepsia. The patientthen resets the PEDP device to the medium setting, and then to the lowsetting. Eventually, the patient experiences hunger and resets the PEDPdevice to the medium setting. In some embodiments, this protocol isdriven by a therapy intensity scale, such as 1 to 5 or 1 to 10, or agraphic on the display of the companion device. In some embodiments,manual operation using low, medium, and high settings is coupled withthe protocols described with reference to FIGS. 21C-25 to establishbaseline PEDP device settings.

FIG. 26 is a flow chart illustrating the steps involved in yet otherembodiments of methods of using an neuro-stimulation device to suppressappetite in a patient. At step 2602, a patient receives instructionsfrom a medical professional, receives a percutaneous electro-dermalpatch (PEDP) device, and downloads a patient diary application to acompanion device, such as a smartphone. Optionally, at step 2604, thepatient gets the PEDP implanted immediately, turns it on, and pairs itwith the companion device such that the companion device beginsrecording appetite, hunger, and well-being parameters in the patientdiary application. In various embodiments, the PEDP is implanted withinthe patient's body by the medical professional or self-implanted by theuser himself. In one embodiment, the PEDP then initiates defaultparameter setting therapy (i.e. every other day, 1×/day for 30 min) withno patient input required at step 2612. The patient diary applicationthen accumulates key data, such as appetite, hunger, and well-being(i.e. nausea, dyspepsia, energy level, weakness/fatigue) over apredefined time period at step 2616. After a minimum time period (i.e. 3days) has elapsed at step 2618, the patient diary application initiatesa modification to the default parameter setting, which may or may notresult in immediate stimulation, wherein the modification may include anincrement or a decrement to any stimulation or timing variable.

Alternatively, in another embodiment, following step 2604 wherein thepatient gets the PEDP implanted immediately, the patient diaryapplication provides the patient various options (i.e. high, medium, andlow appetite control) at step 2614 and, based upon the selected option,initiates a partially tailored parameter setting. The patient diaryapplication then continues to accumulate key data and initiate parametersetting modifications, as detailed in steps 2616 and 2618 respectively.

Optionally, in another embodiment, following step 2602 wherein thepatient receives the PEDP and downloads the patient diary application,the patient does not wear the PEDP immediately at step 2606, but firstturns the PEDP on, pairs it with the companion device, and beginsrecording key data parameters, such as appetite, hunger, and well-being,in the patient diary application. At step 2622, once the patient diaryapplication has accumulated key data over a predefined time period, thepatient is instructed by the application to wear the PEDP. Then, at step2624, once the companion device receives confirmation that the PEDP isbeing worn, the patient diary application initiates a custom stimulationprotocol developed by the patient diary application based on theaccumulated data, which may or may not result in immediate stimulation.Based on on-going key data input, at step 2626, the patient diaryapplication may initiate further modifications to the parametersettings, which may or may not result in immediate stimulation, whereinthe modifications may include an increment or a decrement to anystimulation or timing variable.

Still optionally, in another embodiment, following step 2602 wherein thepatient receives the PEDP and downloads the patient diary application,the patient does not self-implant or get the PEDP implanted by aphysician immediately at step 2608, but first turns the PEDP on, pairsthe PEDP with the companion device, pair the companion device withanother wearable device, for example, a device, with physiologicalsensors, configured to be worn on the human body, such as around thewrist, in order to monitor, acquire, record, and/or transmit thephysiological data, and begins recording key data parameters, such asappetite, hunger, and well-being, as well as data from the otherwearable device, such as fitness/exercise, in the patient diaryapplication. At step 2632, once the patient diary application hasaccumulated key data and data from the other wearable device over apredefined time period, the patient is instructed by the application towear the PEDP. In various embodiments, the PEDP device is eitherself-implanted by the patient himself or is implanted by a physician ormedical personnel. Then, at step 2634, once the companion devicereceives confirmation that the PEDP is being worn, the patient diaryapplication initiates a custom stimulation protocol developed by thepatient diary application based on all accumulated data, which may ormay not result in immediate stimulation. Based on on-going key datainput and on-going input from the other wearable device, at step 2636,the patient diary application may initiate further modifications to theparameter settings, which may or may not result in immediatestimulation, wherein the modifications may include an increment or adecrement to any stimulation or timing variable.

FIG. 27 is a flow chart illustrating the steps involved in a using anneuro-stimulation device and a companion device, paired with a separatemonitoring device, to suppress appetite in a patient, in accordance withone embodiment of the present specification. At step 2702, the patientobtains a PEDP from a medical professional. The patient pairs acompanion device with the PEDP and with a separate monitoring device atstep 2704. The separate monitoring device is configured to measure aplurality of physiological parameters, including, but not limited to,patient weight, body fat, lean mass, and BMI, and wirelessly transmitmonitored data to the companion device. The patient then gets the deviceimplanted on his body by the medical professional at step 2706.Alternatively, the patient self-implants the device on his body at step2706. At step 2708, the companion device sets the PEDP into a defaultstimulation mode based on initial physiological data gathered from theseparate monitoring device. Based on on-going data gathering an input,the companion device continually modifies the electrical stimulationprovided by the PEDP in an effort to suppress appetite in the patient atstep 2710. Optionally, at step 2712, the patient manually adjustsstimulation parameters based on patient well-being, for example,lowering stimulation parameters if the patient is experiencing nausea,dyspepsia or discomfort at the stimulation site.

FIG. 28 is a flow chart illustrating the steps involved in still anotherembodiment of a method of using an neuro-stimulation device to suppressappetite in a patient. At step 2802, the patient obtains a percutaneouselectro-dermal patch (PEDP) device and pairs the EPD device with acompanion device, such as a smartphone, and a separate device, forexample, a device, with physiological sensors, configured to be worn onthe human body, such as around the wrist, in order to monitor, acquire,record, and/or transmit the physiological data. In some embodiments,pairing with the separate device can be done anytime within a treatmentcycle. In some embodiments, a treatment cycle lasts 3 months. At step2804, the device is set into a default operational mode. In someembodiments, the default operational mode includes the stimulationparameters and parameter ranges listed above with respect to FIG. 21Cand includes daily stimulation.

The PEDP device is implanted on the patient's body at step 2806. Inaccordance with various embodiments, the PEDP device is implanted withinthe patient's body by a medical professional or self-implanted by theuser himself At step 2808, the companion device accumulates patientvariable data, including, but not limited to, actual eating and mealsprofile of the user such as the time of consumption of a meal in a dayand the type and amount of food eaten at the meal, standard regulareating and meals routine of the user, such as a standard diet plan (suchas, but not limited to, Mediterranean, Zone Diet, Atkins Diet, KetogenicDiet, Intermittent Fasting, Jenny Craig, and Custom Plan), appetite,hunger, well-being, weight, and calories expended/weight loss, in apatient diary over a predefined period of time. In some embodiments, thecompanion device accumulates data over a range of 1 to 7 days. In oneembodiment, the companion device accumulates data for 3 days. Then, atstep 2810, the companion device drives stimulation therapy wirelesslythrough the PEDP device based on accumulated patient diary data over thetreatment cycle.

During the treatment cycle, if the patient has a positive or surplusenergy balance (representative of more actual calories consumed incomparison to the calories expended) over a predefined period of time,for example, 3 days, the companion device ramps up stimulationparameters (such as, by increasing the stimulation duration, intensityand/or number of sessions) at step 2812. During the treatment cycle, ifthe patient exceeds the glycemic load (calculated based on the patient'sactual eating and meals profile input into the patient diary), comparedto the allowed glycemic load as estimated based on the patient'sstandard diet plan, over a predefined period of time, for example, 3 to5 days, the companion device ramps up stimulation parameters at step2814. Alternatively or additionally, at steps 2812 and 2814, thecompanion device ramps up stimulation parameters if the patient recordsan appetite diary entry with a score of 5, for example, for 3 to 5 days,indicative of poor or no dietary compliance with reference to thepatient's standard diet plan. Thus, in some embodiments, the HealthManagement application uses the appetite parameter, which is indicativeof the patient's dietary compliance, to assess if the patient is likelyto be at a surplus energy balance and exceed the allowable glycemicload.

During the treatment cycle, if the patient exceeds the total number ofmeals per day over a predefined period of time, compared to the numberof meals allowed according to the patient's standard diet plan, thecompanion device may include additional stimulation sessions just prior(for example, a half hour or an hour prior) to the extra meal events atstep 2816. At step 2818, if the patient overeats at a specific time andcontinues to depict such overeating behavior over a predefined period oftime, for example, 3 to 5 days, the companion device may change thetiming of stimulation to just prior (for example, a half hour or an hourprior) to the overeating meal event or time or may include an additionalstimulation session just prior to the overeating meal event. In someembodiments, the energy balance and glycemic load are calculated forevery meal of the day, which in turn enables calculation of the mealthat contributes the highest percentage of calories (or energy surplus)and glycemic load for the day. This meal, which contributes the highestpercentage of calories and glycemic load per day over a predefinedperiod of time, is identified as the overeating meal event.

During the treatment cycle, if the patient stops exercising for apredefined period of time, for example 3 to 5 days, or if the patienthas an exercise score of 5 (FIG. 12), indicating the least level ofexpected exercising and therefore calories expended, and is also at asurplus energy balance for a predefined period of time (for example 3 to5 days), the companion device ramps up stimulation parameters at step2820. At step 2822, following a treatment course or cycle, once thepatient has lost sufficient weight or achieved a target weight, thecompanion device modifies stimulation parameters to a maintenance modewherein the stimulation parameters such as stimulation intensity,duration and number of sessions are all lowered.

Optionally, at step 2824, the companion device provides the patient withthe option of sharing his results via social media with designatedfriends and family. In an alternate embodiment, the companion devicefirst accumulates patient diary data before the PEDP device is set intothe default operation mode. Referring to FIG. 28, in this alternateembodiment, step 2808 is performed prior to step 2804. The remainingsteps proceed in the same order.

Therapeutic Objectives

In various embodiments, the systems and methods of the presentspecification employ a percutaneous electro-dermal patch that providespre-programmed and/or customized stimulation protocols to induce changesin antral and gastric motility to slow passage of food. In variousembodiments, a Health Management application software, as describedabove, provides and/or enables the programming, either pre-programmed orset ‘on demand’ by the patient or medical personnel (in real time), of aplurality of therapeutic goals which are also customizable or adjustablein order to modulate gut hormones, modulate gut microbiota, assessantral and gastric motility, suppress appetite, achieve dietarycompliance, suppress hunger, or elevate fullness, satiation, or satiety.It should be noted herein that any or a plurality of the methods of useor treatment examples provided above may be employed to achieve thetherapeutic objectives.

It should also be noted that the percent changes in value listed beloware represented by the following formula: [(New Value)−(Old Value)]/(OldValue)]. Thus, where a certain parameter is measured in percentage, thepercentage change is reflected by the above formula and not a deltavalue.

The following are a plurality of non-limiting, exemplary goals:

In some embodiments, after at least one stimulation session ordeterminable time period after when stimulation terminates, the rate,level or amount of any patient parameter, as discussed throughout thisspecification is modified relative to the rate, level or amount of thatpatient parameter before stimulation. In one instance, after at leastone stimulation session or determinable time period after whenstimulation terminates, the rate, level or amount of that patientparameter is reduced relative to the rate, level or amount of thatpatient parameter before stimulation. In another instance, after atleast one stimulation session or determinable time period after whenstimulation terminates, the rate, level or amount of that patientparameter is increased relative to the rate, level or amount of thatpatient parameter before stimulation.

In some embodiments, after stimulation terminates, or at least oneminute from when stimulation terminates, the patient experiences adecrease in appetite or hunger by at least 5%.

In some embodiments, after at least one minute from when stimulationterminates or after at least one stimulation session, the patientexperiences a decrease in appetite or hunger such that it is equal to,or less than, 95% of the pre-stimulation appetite or hunger levels.

In some embodiments, after at least one minute from when stimulation isinitiated, the patient experiences a perceptible decrease in appetite orhunger.

In some embodiments, after at least one minute from when stimulation isinitiated, the patient experiences an increase in satiety, satiation orfullness levels by at least 5%.

In some embodiments, after at least one minute from when stimulationterminates or after at least one stimulation session, the patientexperiences an increase in satiety, satiation or fullness levels suchthat it is equal to, or greater than, 105% of the pre-stimulationsatiety, satiation or fullness levels.

In some embodiments, after at least one stimulation session, a patient'scompliance with a target daily caloric intake increases relative to thepatient's compliance with the target daily caloric intake beforestimulation.

In some embodiments, the systems and methods of the presentspecification result in a decrease in the post-stimulation daily caloricintake of a patient relative to a pre-stimulation daily caloric intakeof the patient, wherein the pre-stimulation daily caloric intake is afunction of an amount of calories consumed by the patient over a firstpredefined period of time prior to stimulation, and wherein thepost-stimulation daily caloric intake is a function of an amount ofcalories consumed by the patient over a second predefined period of timeequal in duration to the first predefined period of time, afterstimulation is initiated. For example, the decrease may be quantified asequal to or less than 99% of the pre-stimulation caloric intake, wherethe caloric intake decreases to a range of 600 to 1600 calories,decreases from over 2000 calories per day to less than 2000 calories perday, or decreases from over 1600 calories per day to less than 1600calories per day.

In some embodiments, after at least one stimulation session, an amountor rate of a patient's antral motility, gastric motility, gastricemptying, hunger or appetite level is modified, relative to thecorresponding amount before stimulation.

In some embodiments, after at least one stimulation session, the rate ofa patient's antral motility, gastric motility, or gastric emptying ismodified relative to the rate of the patient's antral motility, gastricmotility, or gastric emptying before stimulation, and preferably therate of a patient's antral motility, gastric motility, or gastricemptying is reduced relative to the rate of the patient's antralmotility, gastric motility, or gastric emptying before stimulation.

In some embodiments, a patient's appetite or hunger level, in a firststate, is greater that the appetite or hunger in a second state, whereinthe first state is defined by a first area under the curve (AUC)corresponding to a pre-stimulation appetite or hunger level and thesecond state is defined by a second AUC corresponding to apost-stimulation appetite or hunger level, and wherein the first AUCdiffers from the second AUC by at least 5%, thereby representing adecrease in the appetite or hunger level of the patient.

In some embodiments, a patient's satiety, satiation or fullness level,in a first state, is less than the satiety, satiation or fullness levelin a second state, wherein the first state is defined by a first AUCcorresponding to a pre-stimulation satiety, satiation or fullness leveland the second state is defined by a second AUC corresponding to apost-stimulation satiety, satiation or fullness level, and wherein thefirst AUC differs from the second AUC by at least 5%, therebyrepresenting an increase in the satiety, satiation or fullness level ofthe patient.

In some embodiments, after at least one stimulation session, an amountof a patient's satiety, satiation or fullness levels increases relativeto the corresponding amount before stimulation.

In some embodiments, after at least one stimulation session, a patient'sappetite or hunger level decreases, over a predefined period of time,relative to the patient's appetite or hunger level before stimulationand the patient's nausea and/or dyspepsia level does not increase, overthe predefined period of time, relative to the patient's nausea levelbefore stimulation, wherein the stimulation does not cause the patientto experience a pain sensation.

In some embodiments, after at least one stimulation session, a patient'ssatiety, satiation or fullness level increases, over a predefined periodof time, relative to the patient's satiety, satiation or fullness levelbefore stimulation and the patient's nausea and/or dyspepsia level doesnot increase, over the predefined period of time, relative to thepatient's nausea level before stimulation, wherein the stimulation doesnot cause the patient to experience a pain sensation.

In some embodiments, after at least one stimulation session, a patient'stotal body weight reduces by at least 1% relative to the patient's totalbody weight before stimulation. In some embodiments, after at least onestimulation session, a patient's total body weight reduces by at least3% relative to the patient's total body weight before stimulation. Insome embodiments, after at least one stimulation session, a patient'stotal body weight reduces by at least 1% relative to the patient's totalbody weight before stimulation and the patient's well-being level doesnot reduce more than 5% relative to the patient's well-being levelbefore stimulation. In some embodiments, after at least one stimulationsession, a patient's total body weight reduces by at least 3% relativeto the patient's total body weight before stimulation and the patient'swell-being level does not reduce more than 5% relative to the patient'swell-being level before stimulation.

In some embodiments, after at least one stimulation session, a patient'spre-prandial ghrelin level reduces by at least 1%, and preferably atleast 3%, relative to the patient's pre-prandial ghrelin level beforestimulation. In some embodiments, after at least one stimulationsession, a patient's post-prandial ghrelin level reduces by at least 1%,and preferably at least 3%, relative to the patient's post-prandialghrelin level before stimulation.

In some embodiments, after at least one stimulation session, apost-stimulation ghrelin level of a patient decreases by at least 1%,and preferably at least 3%, relative to a pre-stimulation ghrelin levelof the patient, wherein the pre-stimulation ghrelin level is measuredprior to stimulation and wherein the post-stimulation ghrelin level ismeasured more than ten weeks after the at least one stimulation session.

In some embodiments, after at least one stimulation session, the levelof a patient's glucagon-like peptide-1, leptin, serotonin, peptide YY,beta-endorphin levels, resting metabolic rate, and/or cholecystokininincreases relative to the corresponding level of a patient'sglucagon-like peptide-1, leptin, serotonin, peptide YY, beta-endorphinlevels, resting metabolic rate, and/or cholecystokinin beforestimulation.

In some embodiments, after at least one stimulation session, the levelof a patient's triglycerides, cholesterol, lipopolysaccharides, and/ormotilin-related peptide decreases relative to the corresponding level ofa patient's triglycerides, cholesterol, lipopolysaccharides, and/ormotilin-related peptide.

In some embodiments, after at least one stimulation session, a patient'sglucagon-like peptide-1 level increases by at least 1%, and preferablyat least 3%, relative to the patient's glucagon-like peptide-1 levelbefore stimulation.

In some embodiments, after at least one stimulation session, a patient'sleptin level increases by at least 1%, and preferably at least 3%,relative to the patient's leptin level before stimulation.

In some embodiments, after at least one stimulation session, a patient'sserotonin level increases by at least 1%, and preferably at least 3%,relative to the patient's serotonin level before stimulation.

In some embodiments, after at least one stimulation session, a patient'speptide YY level increases by at least 1%, and preferably at least 3%,relative to the patient's peptide YY level before stimulation.

In some embodiments, after at least one stimulation session, a patient'sbeta-endorphin level increases by at least 1%, and preferably at least3%, relative to the patient's beta-endorphin level before stimulation.

In some embodiments, after at least one stimulation session, a patient'sresting metabolic rate increases by at least 1%, and preferably at least3%, relative to the patient's resting metabolic rate before stimulation.

In some embodiments, after at least one stimulation session, a patient'scholecystokinin level increases by at least 1%, and preferably at least3%, relative to the patient's cholecystokinin level before stimulation.

In some embodiments, after at least one stimulation session, a patient'slipopolysaccharide level reduces by at least 1%, and preferably at least3%, relative to the patient's lipopolysaccharide level beforestimulation. In some embodiments, a reduction in the lipopolysaccharidelevel also reduces metabolic inflammation and insulin resistance.

In some embodiments, after at least one stimulation session, a patient'smotilin-related peptide level reduces by at least 1%, and preferably atleast 3%, relative to the patient's motilin-related peptide level beforestimulation.

In some embodiments, after at least one stimulation session, a patient'striglycerides level reduces by at least 1%, and preferably at least 3%,relative to the patient's triglycerides level before stimulation.

In some embodiments, after at least one stimulation session, a patient'sdegree of glycemia improves by at least 1%, and preferably at least 3%relative to the patient's degree of glycemia before stimulation.

In some embodiments, after at least one stimulation session, anon-diabetic or a non-pre-diabetic patient's glucose is reduced to afasting level of less than 100 mg/dl, reducing the overall changes ofthe patient developing pre-diabetes in the future.

In some embodiments, after at least one stimulation session, a patient'sglycemic control is improved. In some embodiments, after at least onestimulation session, a patient's glycemic control is modified relativeto the patient's glycemic control before stimulation, and preferably thepatient's glycemic control is increased relative to the patient'sglycemic control before stimulation. In some embodiments, after at leastone stimulation session, the level of hemoglobin A1C decreases by atleast 1%, and preferably at least 3% relative to the patient's level ofhemoglobin A1C before stimulation. In some embodiments, after at leastone stimulation session, the level of hemoglobin A1C decreases by ≥5%relative to the patient's level of hemoglobin A1C before stimulation. Insome embodiments, after at least one stimulation session, the level ofhemoglobin A1C decreases by 0.5% relative to the patient's level ofhemoglobin A1C before stimulation. Because hemoglobin A1C is measured interms of percentage, it should be noted that what is described here isthe percentage change relative to its level before stimulation. Forexample, if the baseline hemoglobin A1C level is measured at 7%, a 5%decrease is calculated as a decrement of 0.35% and therefore a decreasedhemoglobin A1C level of 6.75%.

In some embodiments, after at least one stimulation session, a patient'sglucose homeostasis improves by at least 1%, and preferably at least 3%relative to the patient's glucose homeostasis before stimulation.Optionally, glucose homeostasis is quantified by decreasing HOMA-IR(Homeostasis Model Assessment—estimated Insulin Resistance) by ≥5%compared to a baseline HOMA-IR and is calculated as described above withrespect to hemoglobin A1C. In some T2DM patients, after at least onestimulation session, fasting blood glucose is decreased by 20 mg/dl.

In some embodiments, after at least one stimulation session, the patientexperiences a decrease in a fasting plasma insulin level of ≥5% comparedto a baseline fasting plasma insulin level.

In some embodiments, after at least one stimulation session, the patientexperiences a decrease in a fasting plasma glucose level of ≥5% comparedto a baseline fasting plasma glucose level.

In some embodiments, after at least one stimulation session, a patient'sdegree of insulin resistance is modified relative to the patient'sdegree of insulin resistance before stimulation, and preferably thepatient's degree of insulin resistance is increased relative to thepatient's degree of insulin resistance before stimulation. In someembodiments, after at least one stimulation session, a patient's degreeof insulin resistance improves by at least 1%, and preferably at least3% relative to the patient's degree of insulin resistance beforestimulation.

In some embodiments, after at least one stimulation session, a patient'slevel of total blood cholesterol decreases by at least 1%, andpreferably at least 3%, relative to the patient's level of total bloodcholesterol before stimulation.

In some embodiments, after at least one stimulation session, acomposition of a patient's gut microbiota is modified relative to acomposition of a patient's gut microbiota before stimulation. In someembodiments, after at least one stimulation session, a composition of apatient's gut microbiota modulates from a first state to a second state,wherein the first state has a first level of bacteroidetes and a firstlevel of firmicutes, wherein the second state has a second level ofbacteroidetes and a second level of firmicutes, wherein the second levelof bacteroidetes is greater than the first level of bacteroidetes by atleast 1%, and preferably at least 3%, and wherein the second level offirmicutes is less than the first level of firmicutes by at least 1%,and preferably at least 3%.

In some embodiments, after at least one session of stimulation session,the patient experiences a modification, and preferably, a perceptibledecrease in appetite or hunger which lasts for at least one day.

In some embodiments, a patient's appetite is reduced by 5% over at least1 day of stimulation therapy.

In some embodiments, after at least one session of stimulation, apatient reports “improved” dietary compliance, wherein dietarycompliance is achieving a daily caloric consumption target. In someembodiments, “improved” dietary compliance is at least 5% closer to adefined or set daily calorie consumption target using the PEDP device ofthe present specification.

In some embodiments, a patient has reached a therapeutic goal if theyachieve greater than at least 1%, and more preferably 2%, 5%, 10%, andany increment therein, TWL (Total Weight Loss) or at least 1%, and morepreferably 2%, 5%, 10%, and any increment therein, EWL (Excess WeightLoss) in six months of stimulation therapy.

In some embodiments, a patient has reached a therapeutic goal if theyare able to change their metabolism rate (such as RMR or BMR) by 10%. Insome embodiments, a stimulation therapy is intended to affect at least5% improvement in RMR.

In some embodiments, application of electrical stimulation via the PEDPembodiments disclosed herein result in a person having an alteredperception of gastric fullness or emptiness. Specifically, when the PEDPtherapy is applied, the stimulation parameters are selected such that,after at least one stimulation session, the perception of gastricfullness or gastric emptiness of the patient increases by at least 1%relative to the perception of gastric fullness or gastric emptiness ofthe patient before stimulation. This may be measured over a single day,week, month or other time period.

In some embodiments, application of electrical stimulation via the PEDPembodiments disclosed herein result in a person having increasedexercise output, defined as the amount of calories burned in a giventime period or steps taken in a given time period. Specifically, whenthe PEDP therapy is applied, the stimulation parameters are selectedsuch that, after at least one stimulation session, exercise output ofthe patient increases by at least 1% relative to the exercise output ofthe patient before stimulation. This exercise output may be measuredover a single day, week, month or other time period.

Achieving Dietary Compliance

In one embodiment, use of the PEDP device, in accordance with themethods described herein, result in patients being able to better complywith a predefined dietary regime, including being better able torestrict daily caloric intake to a predefined amount, being better ableto adhere to a diet designed to maximize particular nutritionalcomponents, such as vitamins, minerals, and proteins, and decreaseundesirable nutritional components, such as carbohydrates, fat, andsugars, and being better able to adhere to a diet designed to have aglycemic index that is equal to or less than a predefined amount. Thepresent specification facilitates adhering to dietary objectives foroverweight (body mass index of 25-29.9) or obese (body mass index of 30or greater) individuals, particularly given that willpower alone or evenwillpower with exercise is an ineffectual approach to dietary complianceand either weight loss or weight management.

Therapeutically, the PEDP device can be used in conjunction withpredefined diet plans, comprising a nutritional profile, a set of foods,and/or a maximum number of calories, to ensure that a patient adheres tothe predefined plan.

Therefore, in one embodiment, the present specification enablesincreased dietary compliance. A patient is provided the PEDP device,adheres it to his or her epidermal layer, and initiates a stimulationregime. The patient also receives a diet plan, either manually orelectronically into an application executing on an external device, thatdefines a diet plan. The diet plan may establish a maximum daily caloricintake, such as between 600 and 1600 calories, may require a particularnutritional profile, such as a certain number or type of vegetables,proteins, and/or supplements, and/or may require the avoidance ofcertain types of foods, such as carbohydrates, sugars, and/or foods withhigh glycemic indexes. The parameters of the diet plan may be based onreceiving, electronically into an application executing on an externaldevice or manually, an indication of how active the patient is(sedentary, moderately active, active), the patient's gender, thepatient's age, the patient's weight, the patient's height, the patient'spercentage of body fat, and/or the patient's body mass index. As thepatient uses the device and records his or her food consumption, eitherinto the program in the external device in communication with the PEDPdevice or into a separate third party program which then transmits theinformation to the program in communication with the PEDP device, theprogram in communication with the PEDP device determines if the patientis complying with the diet regimen. If the patient is not avoidingcertain types of food, not eating a particular nutritional profile,and/or exceeding the maximum daily caloric intake, the program modulatesstimulation parameters in order to decrease appetite and/or hungerlevels and transmits those modulated stimulation parameters to the PEDPdevice, which then increases stimulation strength, duration, and/orfrequency, thereby causing the decrease appetite and/or hunger levelsand enabling the patient to better comply with the diet regimen.Conversely, if the patient is not getting enough calories, the programmodulates stimulation parameters in order to increase appetite and/orhunger levels and transmits those modulated stimulation parameters tothe PEDP device, which then decreases stimulation strength, duration,and/or frequency, thereby causing the increase appetite and/or hungerlevels and, again, enabling the patient to better comply with the dietregimen.

In another embodiment, the present specification enables improveddietary management. One substantial problem that physicians and dietprograms have is keeping a patient on the prescribed diet. The presentspecification enables improved dietary management. A third partymanager, such as a physician or health care provider, provides a patientwith the PEDP device and programs the PEDP device with an initialstimulation regime based upon a prescribed diet plan. The diet plan mayestablish a maximum daily caloric intake, such as in the range of 600 to1600 calories, may require a particular nutritional profile, such as acertain number or type of vegetables, proteins, and/or supplements,and/or may require the avoidance of certain types of foods, such ascarbohydrates, sugars, and/or foods with high glycemic indexes. Theparameters of the diet plan may be based on receiving, electronicallyinto an application executing on an external device or manually, anindication of how active the patient is (sedentary, moderately active,active), the patient's gender, the patient's age, the patient's weight,the patient's height, the patient's percentage of body fat, and/or thepatient's body mass index. As the patient uses the device and recordshis or her food consumption, either into the program in the externaldevice in communication with the PEDP device or into a separate thirdparty program which then transmits the information to the program incommunication with the PEDP device, the program in communication withthe PEDP device determines if the patient is complying with the dietregimen. If the patient is not avoiding certain types of food, noteating a particular nutritional profile, and/or exceeding the maximumdaily caloric intake, the third party manager may modulate stimulationparameters in order to decrease appetite and/or hunger levels andtransmits those modulated stimulation parameters to the PEDP device,which then increases stimulation strength, duration, and/or frequency,thereby causing the decrease appetite and/or hunger levels and enablingthe patient to better comply with the diet regimen. Conversely, if thepatient is not getting enough calories, the third party manager maymodulate stimulation parameters in order to increase appetite and/orhunger levels and transmit those modulated stimulation parameters to thePEDP device, which then decreases stimulation strength, duration, and/orfrequency, thereby causing the increase appetite and/or hunger levelsand, again, enabling the patient to better comply with the diet regimen.

In another embodiment, the present specification enables improveddietary maintenance and preventing the regaining of weight. Aftermeeting a weight goal, through any of the aforementioned treatmentmethods, the patient's diet plan is adjusted to a new diet planreflecting a weight maintenance, instead of a weight loss, objective.Such a diet plan, which may be received either manually orelectronically into an application executing on an external device, mayestablish a higher maximum daily caloric intake than the previous dietplan, such as between 1600 and 2800 calories, a different nutritionalprofile, and/or less emphasis on avoiding of certain types of foods,such as carbohydrates, sugars, and/or foods with high glycemic indexes.The parameters of the new diet plan may be based on receiving,electronically into an application executing on an external device ormanually, an indication of how active the patient is (sedentary,moderately active, active), the patient's gender, the patient's age, thepatient's weight, the patient's height, the patient's percentage of bodyfat, and/or the patient's body mass index. As the patient uses thedevice and records his or her food consumption, either into the programin the external device in communication with the PEDP device or into aseparate third party program which then transmits the information to theprogram in communication with the PEDP device, the program incommunication with the PEDP device determines if the patient iscomplying with the new diet regimen. If the patient is not avoidingcertain types of food, not eating a particular nutritional profile,and/or exceeding the new maximum daily caloric intake, the programmodulates stimulation parameters in order to decrease appetite and/orhunger levels and transmits those modulated stimulation parameters tothe PEDP device, which then increases stimulation strength, duration,and/or frequency, thereby causing the decrease appetite and/or hungerlevels and enabling the patient to better comply with the diet regimen.Conversely, if the patient is not eating enough calories, the programmodulates stimulation parameters in order to increase appetite and/orhunger levels and transmits those modulated stimulation parameters tothe PEDP device, which then decreases stimulation strength, duration,and/or frequency, thereby causing the increase appetite and/or hungerlevels and, again, enabling the patient to better comply with the dietregimen.

Alternatively, instead of modulating the stimulation parameters if thepatient is not avoiding certain types of food, not eating a particularnutritional profile, and/or exceeding the new maximum daily caloricintake, the program, either in direct communication with the PEDPdevice, a remote server, or a third party application executing on anexternal device, may change the diet plan itself by increasing ordecreasing the maximum daily caloric intake, changing the nutritionalprofile, and/or changing what types of foods to avoid.

FIGS. 32A through 32F show charts illustrating how the stimulationtherapy of the present specification affects or modulates a plurality ofpatient variables or parameters such as, weight, BMI (Body Mass Index),appetite, dietary compliance and well-being for a sample of 10 patients.In accordance with an embodiment, the sample of 10 patients, havingweight loss as an objective or goal, were treated with the stimulationtherapy of the present specification over a duration of 4 weeks and thepatients recorded their status on the plurality of variables orparameters throughout the duration of the 4 weeks using their companiondevices. As shown in FIG. 32A, the 10 patients also exercised throughthe duration of 4 weeks and recorded their exercise scores 3205 usingtheir companion devices (as described earlier with reference to FIG.12). The bar graph 3210 shows median exercise scores per week,calculated from the exercise scores of the sample of 10 patients, whilethe line graphs 3215 show exercise scores per week of each of the 10patients. As can be observed from the bar graph 3210, the medianexercise scores 3211, 3212, 3213 improved during the second, third andfourth weeks.

FIG. 32B shows charts illustrating how the weight parameter, for thesample of 10 patients, varied during the course of the 4 weeks, whilethe patients exercised, received stimulation therapy and recorded theirweight using their companion devices (as described earlier withreference to FIG. 15). The bar graph 3220 shows median weights per week,calculated from the weights of the sample of 10 patients, while the linegraphs 3225 show weights per week of each of the 10 patients. As can beobserved from the bar graph 3220, the median weights 3222, 3223, 3224,3226 continued to reduce during the first, second, third and fourthweeks relative to the median weight 3221 at the baseline (that is, priorto receiving stimulation therapy).

FIG. 32C shows charts illustrating how the BMI parameter, for the sampleof 10 patients, varied during the course of the 4 weeks, while thepatients exercised and received stimulation therapy. The bar graph 3230shows median BMI per week, calculated from the BMIs of the sample of 10patients, while the line graphs 3235 show BMIs per week of each of the10 patients. As can be observed from the bar graph 3230, the median BMIs3232, 3233, 3234, 3236 continued to reduce during the first, second,third and fourth weeks relative to the median BMI 3231 at the baseline(that is, prior to receiving stimulation therapy).

FIG. 32D shows charts illustrating how the appetite parameter, for thesample of 10 patients, varied during the course of the 4 weeks, whilethe patients exercised, received stimulation therapy and recorded theirappetite scores 3247 using their companion devices (as described earlierwith reference to FIG. 11). The bar graph 3240 shows median appetitescores per week, calculated from the appetite scores of the sample of 10patients, while the line graphs 3245 show appetite scores per week ofeach of the 10 patients. As can be observed from the bar graph 3240, themedian appetite scores 3242, 3243, 3244, 3246 continued to reduce duringthe first, second, third and fourth weeks relative to the medianappetite score 3241 at the baseline (that is, prior to receivingstimulation therapy).

FIG. 32E shows charts illustrating how the dietary compliance parameter,for the sample of 10 patients, varied during the course of the 4 weeks,while the patients exercised, received stimulation therapy and recordedtheir dietary compliance scores 3257 using their companion devices. Thebar graph 3250 shows median dietary compliance scores per week,calculated from the dietary compliance scores of the sample of 10patients, while the line graphs 3255 show dietary compliance scores perweek of each of the 10 patients. As can be observed from the bar graph3250, the median dietary compliance scores 3252, 3253, 3254, 3256improved during the first, second, third and fourth weeks relative tothe median dietary compliance score 3251 at the baseline (that is, priorto receiving stimulation therapy). The graph 3250 highlights keyadvantages of the wearable neuro-stimulation device of the presentspecification, specifically in terms of greater patient independence andimproved patient compliance to stimulation protocols, with resultantincreased dietary compliance.

FIG. 32F shows charts illustrating how the well-being parameter, for thesample of 10 patients, varied during the course of the 4 weeks, whilethe patients exercised, received stimulation therapy and recorded theirwell-being scores 3267 using their companion devices (as describedearlier with reference to FIG. 16). The bar graph 3260 shows medianwell-being scores per week, calculated from the well-being scores of thesample of 10 patients, while the bar graphs 3265 show variation inwell-being scores for a number of patients (y-axis) reporting symptomsof nausea/abdominal pain at each week. As can be observed from the bargraph 3260, the median well-being scores 3262, 3263, 3264, 3266 remainedstable during the first, second, third and fourth weeks relative to themedian well-being score 3261 at the baseline (that is, prior toreceiving stimulation therapy) although there were occasionaldeterioration of well-being scores per week (such as the well-beingscores 3268, 3269, 3270 for 4, 2 and 3 patients respectively) for somepatients, as can be observed from the bar graphs 3265.

It should be appreciated that the pre-stimulation levels of theplurality of patient variables or parameters (such as, but not limitedto, weight, BMI (Body Mass Index), appetite, dietary compliance andwell-being) are measured using a scale (such as a VAS) at predefinedtimes of the day over a first predefined period of time (such as 4weeks, for example), and the post-stimulation levels of the patientvariables or parameters are measured, after stimulation is initiated,using the scale at the predefined times of the day over a secondpredefined period of time, equal in duration to the first predefinedperiod of time.

It should be appreciated that each of the pre-stimulation andpost-stimulation levels, profiles or measurements may be assessed bycomparing data from a single individual or by first aggregatingpre-stimulation data from multiple individuals and post-stimulation datafrom multiple individuals and comparing the two aggregated data sets.Additionally, it should be appreciated that the effects of stimulationmay be assessed by comparing measured parameters, as described above,from either an individual or group (in the form of aggregated data) to acontrol individual or group which has not undergone stimulation. In suchcases, one would be comparing post-stimulation effects to no stimulationin a different individual or group of individuals (control) as opposedto comparing post-stimulation effects to pre-stimulation measurementsfrom the same individual or group of individuals.

Telemedicine

As discussed earlier, the neuro-stimulation device is in datacommunication with and controlled by the companion device. The companiondevice is further capable of being in data communication with one ormore remote patient care facilities and/or patient care personnelenabling telehealth or e-health and therefore allowing health careprofessionals to evaluate, diagnose and treat patients in remotelocations using telecommunications technology.

In accordance with an aspect of the present specification, the user'splurality of health related information, such as the user's hungerprofile, standard eating and meals profile, actual eating and mealsprofile, energy balance, weight trends, glucose data, daily or periodicscores related to hunger, appetite, exercise and well-being, stimulationinduced nausea, dyspepsia and habituation events, including stimulationprotocols, setting and parameters are recorded, archived and stored bythe Health Management application software on the Cloud (for example).In various embodiments, such recorded and archived health relatedinformation as well stimulation protocols, settings and parameters ofthe user are communicated to one or more remote care facilities and/orpatient care personnel in real time, on-demand and/or periodically.

This enables the user to communicate his health status, trends,treatment or therapy details as well as therapeutic outcomes to theremote care facility and/or patient care personnel for evaluation,advice, support and further treatment and/or medication options. Forexample, weight loss programs focused on diets often fail due to weightgain after the termination of the program. However, the HealthManagement application software, which may be HIPAA compliant, enablescontinuous weight maintenance by: enabling remote monitoring of theuser's weight, blood glucose, blood pressure, and overall activitylevel, for example; supporting a plurality of modes of communicationsuch as, but not limited to, video-conferencing, tele-conferencing,email, and chat to enable interactive, real-time and/or asynchronousweight maintenance related advice or stimulation regimen for the user.For example, the user's nutrition specialist, fitness trainer and/or aconcierge service associated with the PEDP device and Health Managementapplication of the present specification may access, process and analyzethe user's health related information and provide interventions in theform of adjusted or modified stimulation parameters, settings andprotocols; modifications to exercising routines, forms, frequency andperiod; and/or adjustments to the user's dietary plan.

Hydrolysis of Adipose Tissues

In accordance with an aspect, stimulation of the sympathetic nervesusing the PEDP device of the present specification allows forinnervation of white adipose tissue to hydrolyze them. Even after losingweight, there are spots or areas that remain with a high amount ofadipose tissue (for example hip or upper arm or love handles on thetrunk). In some embodiments, these spots or areas are stimulated overlong periods of time, for example daily, to hydrolyze the adipose tissueaccumulated in these spots or areas.

The above examples are merely illustrative of the many applications ofthe methods and systems of present specification. Although only a fewembodiments of the present invention have been described herein, itshould be understood that the present invention might be embodied inmany other specific forms without departing from the spirit or scope ofthe invention. Therefore, the present examples and embodiments are to beconsidered as illustrative and not restrictive, and the invention may bemodified within the scope of the appended claims.

We claim:
 1. An electrical stimulation system configured to modulate at least one of a patient's appetite, hunger, level of satiety, or level of satiation comprising: a percutaneous electrical dermal patch adapted to be adhered to the patient's skin, wherein said electrical dermal patch comprises a controller, at least one electrode adapted to be implanted to a depth of 0.1 mm to 30 mm within said patient's skin, a pulse generator in electrical communication with the controller and said at least one electrode; and a transceiver in communication with at least one of said controller and pulse generator; and a plurality of programmatic instructions, stored in a non-transient computer readable memory of a device physically separate from said percutaneous electrical dermal patch, wherein, when executed, said programmatic instructions acquire patient status data, generate a modulation signal based upon said patient status data, wherein said modulation signal comprises instructions for modulating at least one of a pulse width, a pulse amplitude, a pulse frequency, a pulse shape, a duty cycle, a session duration, and a session frequency, and wirelessly transmit said modulation signal from the device to the transceiver.
 2. The electrical stimulation system of claim 1 further comprising a second electrode adapted to be positioned on a surface of the patient's skin.
 3. The electrical stimulation system of claim 1 further comprising a second percutaneous electrode adapted to be implanted to a depth of 0.1 mm to 30 mm within said patient's skin.
 4. The electrical stimulation system of claim 1 wherein the pulse generator is configured to generate a plurality of electrical pulses and a corresponding electrical field, wherein the electrical field is adapted to penetrate a range of 0.1 mm to 30 mm through the patient's skin.
 5. The electrical stimulation system of claim 4 wherein the electrical field is adapted to contact at least one of the patient's T2 frontal and lateral thoracic dermatome, T3 frontal and lateral thoracic dermatome, T4 frontal and lateral thoracic dermatome, T5 frontal and lateral thoracic dermatome, T6 frontal and lateral thoracic dermatome, T7 frontal and lateral thoracic dermatome, T8 frontal and lateral thoracic dermatome, T9 frontal and lateral thoracic dermatome, or T10 frontal and lateral thoracic dermatome.
 6. The electrical stimulation system of claim 4 wherein the electrical field is adapted to contact at least one of the patient's T2 frontal and lateral thoracic dermatome, T3 frontal and lateral thoracic dermatome, T4 frontal and lateral thoracic dermatome, T5 frontal and lateral thoracic dermatome, T6 frontal and lateral thoracic dermatome, T7 frontal and lateral thoracic dermatome, T8 frontal and lateral thoracic dermatome, T9 frontal and lateral thoracic dermatome, or T10 frontal and lateral thoracic dermatome and is not positioned within a range of 0.1 mm to 25 mm from any one of the patient's T2 posterior thoracic dermatome, T3 posterior thoracic dermatome, T4 posterior thoracic dermatome, T5 posterior thoracic dermatome, T6 posterior thoracic dermatome, T7 posterior thoracic dermatome, T8 posterior thoracic dermatome, T9 posterior thoracic dermatome, or T10 posterior thoracic dermatome.
 7. The electrical stimulation system of claim 4 wherein the electrical field is adapted to contact at least one of the patient's C8 anterior or posterior dermatome located on the patient's hand, wrist, elbow, or fingers, C8 anterior or posterior dermatome located on the patient's arm, C8 dermatome located on the patient's upper trunk, T1 anterior or posterior dermatome located on the patient's arm, T1 anterior or posterior dermatome located on the patient's wrist, elbow, and hand, or T1 anterior or posterior dermatome located on the patient's upper trunk is electrically stimulated.
 8. The electrical stimulation system of claim 1 wherein the plurality of electrical pulses comprise a pulse width in a range of 10 μsec to 100 msec, a pulse amplitude in a range of 100 μA to 500 mA, and a pulse frequency in a range of 1 Hz to 10,000 Hz.
 9. The electrical stimulation system of claim 1 wherein said patient status data comprises at least one of the patient's hunger, the patient's hunger appetite, the patient's satiety level, the patient's satiation level, and a degree of well-being being experienced by the patient.
 10. The electrical stimulation system of claim 9 wherein said well-being level comprises at least one of a degree of nausea being experienced by the patient and a degree of dyspepsia being experienced by the patient.
 11. The electrical stimulation system of claim 1 wherein, when executed, said programmatic instructions acquire a first stimulation protocol and use said first stimulation protocol to generate the modulation signal.
 12. The electrical stimulation system of claim 11 wherein, when executed, said programmatic instructions acquire a second stimulation protocol, wherein said second stimulation protocol is different from the first stimulation protocol, and, using said second stimulation protocol, generate a second modulation signal, wherein said second modulation signal comprises instructions for modulating at least one of the pulse width, the pulse amplitude, the pulse frequency, the pulse shape, the duty cycle, the session duration, and the session frequency.
 13. The electrical stimulation system of claim 12 wherein, when executed, said programmatic instructions wirelessly transmit said second modulation signal from the device to the electrical dermal patch.
 14. The electrical stimulation system of claim 13 wherein the percutaneous electrical dermal patch is configured to use the second modulation signal to modify at least one of said pulse width, pulse amplitude, pulse frequency, pulse shape, duty cycle, session duration, and session frequency to yield a second pulse width, a second pulse amplitude, a second pulse frequency, a second pulse shape, a second duty cycle, a second session duration, or a second session frequency, wherein at least one of the second pulse width is different from the first pulse width, the second pulse amplitude is different from the first pulse amplitude, the second pulse frequency is different from the first pulse frequency, the second pulse shape is different from the first pulse shape, the second duty cycle is different from the first duty cycle, the second session duration is different from the first session duration, and the second session frequency is different from the first session frequency.
 15. The electrical stimulation system of claim 1 wherein said controller, pulse generator, and transceiver are positioned in a first housing and the at least one electrode is positioned outside said first housing.
 16. The electrical stimulation system of claim 15 wherein said first housing is covered by at least one polymer having a hardness measure of 30-70 on a subzero shore scale.
 17. The electrical stimulation system of claim 15 wherein said first housing is encased in at least one polymer having a tensile modulus of 15 to 55 psi.
 18. The electrical stimulation system of claim 1 wherein said controller and transceiver are positioned in a first housing and said pulse generator and the at least one electrode are positioned outside said first housing.
 19. The electrical stimulation system of claim 1 further comprising an adhesive layer positioned on a bottom surface of the electrical dermal patch, such that when the adhesive layer is adhered to the patient's skin, the electrical dermal patch has an average minimum peel strength in a range of 1.3 to 1.7 newtons.
 20. The electrical stimulation system of claim 1 wherein at least one of said pulse width, said pulse amplitude, and said pulse frequency are defined such that, after receiving at least one stimulation session, the appetite of said patient is less than the appetite of said patient prior to receiving said at least one stimulation session.
 21. The electrical stimulation system of claim 1 wherein the percutaneous electrical dermal patch further comprises a power source.
 22. The electrical stimulation system of claim 1 wherein the percutaneous electrical dermal patch further comprises an impedance sensor configured to determine an electrode integrity of the at least one electrode.
 23. The electrical stimulation system of claim 1 wherein the pulse generator is configured to generate a plurality of electrical pulses and a corresponding electrical field, wherein the electrical field is adapted to contact at least one of the patient's C5, C6, C7, C8, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, or T12 dermatomes.
 24. The electrical stimulation system of claim 1 wherein the pulse generator is configured to generate a plurality of electrical pulses and a corresponding electrical field, wherein the electrical field is adapted to contact a portion of at least one of the patient's C5, C6, C7, C8, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, or T12 frontal or lateral dermatomes and wherein the electrical field is not adapted to contact any portion of the patient's C5, C6, C7, C8, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, and T12 posterior dermatomes. 